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Trigeminal neuralgia (TN) is chronic pain caused by damage to the somatosensorial system on the trigeminal nerve or its branches, which involves peripheral and central dysfunction pain pathways. Trigeminal pain triggers disruptive pain in regions of the face, including within and around the mouth. Besides clinical experiences, translating the language of suffering into scientific terminology presents substantial challenges. Due to the complex and multifactorial pathophysiology underlying trigeminal pain, elucidating its social impact presents significant difficulties. Carbamazepine and oxcarbazepine are first-line treatments for TN, achieving approximately 50% pain reduction in 60–70% of treated patients. However, their efficacy is often limited by common side effects, such as dizziness, vertigo, nausea, seizures, and cognitive symptoms. In some cases, patients experience severe side effects, including myelosuppression, hyponatremia, hormonal imbalances, liver toxicity, suicidal ideation, teratogenicity, and other adverse reactions. Given these clinical limitations, the search for new painkiller candidates continues. Hence, we focused this review on salvinorin A (SalA), a natural agonist of κ-opioid receptors (KORs), which demonstrated anti-nociceptive, anti-inflammatory, and anti-neuropathic properties in various experimental models of the spinal sensory system. Furthermore, preclinical evidence indicates that SalA does not induce dependence and demonstrates a favorable toxicological and safety profile in comparison with currently marketed opioid drugs. We propose Salvinorin A as a promising candidate for treating trigeminal neuralgia, offering the potential for reduced adverse effects. [ABSTRACT FROM AUTHOR]

Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids – termed oxa-iboga – defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential. Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder. [ABSTRACT FROM AUTHOR]

Salvia divinorum is a hallucinogenic plant native to the Oaxaca in Mexico. The active ingredient for psychotropic effects in this plant is salvinorin A, a potent and highly selective κ‐opioid receptor agonist. Salvinorin A is distinct from other well‐known opioids, such as morphine and codeine, in that it is a non‐nitrogenous diterpenoid with no affinity for μ‐opioid receptor, the prime receptor of alkaloidal opioids. A terpene opioid that selectively targets a new opioid receptor (κ‐opioid receptor) can be instrumental in developing alternative analgesics. Elucidation of the salvinorin A biosynthetic pathway can help bio‐manufacture diverse semi‐synthetic derivatives of salvinorin A but, to date, only two enzymes in the Salvinorin A pathway have been identified. Here, we identify CYP728D26 that catalyzes a C18 oxygenation on crotonolide G, which bears a clerodane backbone. Biochemical identity of CYP728D26 was validated by in vivo reconstitution in yeast, 1H‐ and 13C‐NMR analyses of the purified product, and kinetic analysis of CYP728D26 with a Km value of 13.9 μM. Beyond the single oxygenation on C18, collision‐induced dissociation analysis suggested two additional oxygenations are catalyzed by CYP728D26 to form crotonoldie G acid, although this carboxylic acid form is a minor product. Its close homologue CYP728D25 exhibited a C1‐hydroxylation on the clerodane backbone in a reconstituted yeast system. However, CYP728D25 showed no activity in in vitro assays. This result implies that catalytic activities observed from overexpression systems should be interpreted cautiously. This work identified a new CYP catalyst and advanced our knowledge of salvinorin A biosynthesis. [ABSTRACT FROM AUTHOR]

Salvinorin A is a powerful hallucinogen in humans, and a selective, high efficacy agonist of the kappa‐opioid receptor (κ‐OR). Salvinorin A is the first plant‐derived ligand with high selectivity for κ‐OR over other receptors, its structure is unrelated to any known opioid receptor ligands, even lacking any nitrogenous moieties. Mechanistically and pharmacologically, salvinorin A is distinct from other known hallucinogens in humans, making it the only selective κ‐OR ligand to gain wide‐spread interest outside of research. Structurally, salvinorin A bares a highly functionalized trans‐decalin core, containing two quaternary centers, and is fused to a δ‐lactone baring a furan moiety. Synthetic access of salvinorin A has been elusive due to a highly sensitive epimerizable center at carbon 8 (C8). All these features make salvinorin A a highly challenging synthetic target. With multiple synthetic efforts from around the world, only nine completed syntheses have been achieved to date. This review is intended to provide a look at the key strategies used to achieve the syntheses reported to date. We will summarize the efforts towards the syntheses of salvinorin A starting from Evans in 2007 to Barriault in 2023. [ABSTRACT FROM AUTHOR]

Coleus scutellarioides (L.) Benth. is a popular species in the world, known for its characteristic magnificent colourful leaves. The study has revealed that the contents of rosmarinic acid and caffeic acid are significantly higher in the plant tissues cultivated in vivo than when under in vitro conditions. The performed qualitative and quantitative analyses confirmed the presence (whose averaged content) of salvinorin A (6.65 µg/1 g of fresh plant) and salvinorin B (50.46 µg/1 g of fresh plant) in tissues of Coleus scutellarioides (L.) Benth. of 'Electric lime' variety. The greatest quantities of these compounds were recorded for plants cultivated in vitro on the MS medium enriched with NAA (naphthyl-1-acetic acid) at a concentration of 0.5 mg∙ dm–3. The research detected differences in the amounts of compounds between plants grown in vivo and those cultivated in vitro. Addition of plant growth regulators into the breeding medium under in vitro conditions was found affecting the amounts of compounds in plant tissues. [ABSTRACT FROM AUTHOR]

The objective of this paper is to conduct a systematic thematic review of adverse events, safety, and toxicity of traditional ayahuasca plant preparations and its main psychoactive alkaloids (dimethyltryptamine [DMT], harmine, harmaline, and tetrahydroharmine), including discussing clinical considerations (within clinical trials or approved settings). A systematic literature search of preclinical, clinical, epidemiological, and pharmacovigilance data (as well as pertinent reviews and case studies) was conducted for articles using the electronic databases of PubMed and Web of Science (to 6 July 2023) and PsycINFO, ClinicalTrials.gov, and Embase (to 21 September 2022) and included articles in English in peer-reviewed journals. Additionally, reference lists were searched. Due to the breadth of the area covered, we presented the relevant data in a thematic format. Our searches revealed 78 relevant articles. Data showed that ayahuasca or DMT is generally safe; however, some adverse human events have been reported. Animal models using higher doses of ayahuasca have shown abortifacient and teratogenic effects. Isolated harmala alkaloid studies have also revealed evidence of potential toxicity at higher doses, which may increase with co-administration with certain medications. Harmaline revealed the most issues in preclinical models. Nevertheless, animal models involving higher-dose synthetic isolates may not necessarily be able to be extrapolated to human use of therapeutic doses of plant-based extracts. Serious adverse effects are rarely reported within healthy populations, indicating an acceptable safety profile for the traditional use of ayahuasca and DMT in controlled settings. Further randomized, controlled trials with judicious blinding, larger samples, and longer duration are needed. [ABSTRACT FROM AUTHOR]

Covering: 2000 to 2023 This review presents the exceptional story of ophiobolin A (OphA) and sphaeropsidin A (SphA), a sesterterpene and a diterpene, respectively, which were initially isolated as fungal phytotoxins and subsequently shown to possess other interesting biological activities, including promising anticancer activities. Ophiobolin A is a phytotoxin produced by different fungal pathogens, all belonging to the Bipolaris genus. Initially, it was only known as a very dangerous phytotoxin produced by fungi attacking essential cereals, such as rice and barley. However, extensive and interesting studies were carried out to define its original carbon skeleton, which is characterized by a typical 5 : 8 : 5 ring system and shared with fusicoccins and cotylenins, and its phytotoxic activity on host and non-host plants. The biosynthesis of OphA was also defined by describing the different steps starting from mevalonate and through the rearrangement of the acyclic C-25 precursor lead the toxin is obtained. OphA was also produced as a bioherbicide from Drechslera gigantea and proposed for the biocontrol of the widespread and dangerous weed Digitaria sanguinaria. To date, more than sixty ophiobolins have been isolated from different fungi and their biological activities and structure–activity relationship investigated, which were also described using their hemisynthetic derivatives. In the last two decades, thorough studies have been performed on the potential anticancer activity of OphA and its original mode of action, attracting great interest from scientists. Sphaeropsidin A has a similar story. It was isolated as the main phytotoxin from Diplodia cupressi, the causal agent of Italian cypress canker disease, resulting in the loss of millions of plants in a few years in the Mediterranean basin. The damage to the forest, environment and ornamental heritage are noteworthy and economic losses are also suffered by tree nurseries and the wood industry. Six natural analogues of SphA were isolated and several interesting hemisynthetic derivatives were prepared to study its structure–activity relationship. Surprisingly, sphaeropsidin A showed other interesting biological activities, including antibiotic, antifungal, and antiviral. In the last decade, extensive studies have focused on the anticancer activity and original mode of action of SphA. Furthermore, specific hemisynthetic studies enable the preparation of derivatives of SphA, preserving its chromophore, which showed a noteworthy increase in anticancer activity. It has been demonstrated that ophiobolin A and sphaeropsidin A are promising natural products showing potent activity against some malignant cancers, such as brain glioblastoma and different melanomas. [ABSTRACT FROM AUTHOR]

Rationale: Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. Objectives: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. Results: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. Conclusions: These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control. [ABSTRACT FROM AUTHOR]

Pain is associated with many health problems and a reduced quality of life and has been a common reason for seeking medical attention. Several therapeutics are available on the market, although side effects, physical dependence, and abuse limit their use. As the process of pain transmission and modulation is regulated by different peripheral and central mechanisms and neurotransmitters, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery due to their chemical structural variety and different analgesic mechanisms. Numerous studies suggested that some chemicals from medicinal plants could be alternative options for pain relief and management. Previously, we conducted a literature search aimed at identifying natural products interacting either directly or indirectly with opioid receptors. In this review, instead, we have made an excursus including active ingredients derived from plants whose mechanism of action appears from the literature to be other than the modulation of the opioid system. These substances could, either by themselves or through synthetic and/or semi-synthetic derivatives, be investigated in order to improve their pharmacokinetic characteristics and could represent a valid alternative to the opioid approach to pain therapy. They could also be the basis for the study of new mechanisms of action in the approach to this complex and disabling pathology. [ABSTRACT FROM AUTHOR]

Rationale: Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. Objective: The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. Methods: Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1–3.2 µg/kg/injection), nalfurafine (0.0032–0.1 µg/kg/injection), triazole 1.1 (3.2–100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. Results: Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. Conclusions: These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects, some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated genes' upregulatory cascades, leading it to play a pivotal role in neuroprotective actions while evidently causing neuronal disorders at high doses. Additionally, its anti-inflammatory, antioxidative, antibacterial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve ambiguities about the neuronal effects of kratom and demonstrate its prospects as a therapeutic target for neurological disorders associated with other pharmacological effects. [ABSTRACT FROM AUTHOR]

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05–0.80 μg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05–0.80 μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05–0.80 μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542- 0.30 μg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05–0.80 μg/kg in hemodialysis patients. HSK21542-0.3 μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. [ABSTRACT FROM AUTHOR]

Morphine is a drug that can lead to addiction because of its rewarding effects. The present study investigated the effects of a hydro-ethanolic extract of Echinophora platyloba L. (Apiaceae) on the rewarding effects of morphine. The rewarding effects of morphine and the plant extract were evaluated using a conditioned place preference (CPP) paradigm in mice. Additionally, the effects of administering the plant extract on the expression and acquisition of morphine CPP were investigated. Finally, the role of opioid receptors in the CPP of the plant extract was determined. Both morphine and the extract induced a significant CPP. Furthermore, naloxone could inhibit the CPP of the plant extract. The plant extract had no effect on the expression of morphine CPP, but it significantly inhibited the acquisition of morphine CPP. Consequently, the extract of E. platyloba L. has rewarding effects, which may be mediated through opioid receptors. The extract can also inhibit the acquisition of morphine CPP. [ABSTRACT FROM AUTHOR]

Difelikefalin is a selective kappa opioid receptor agonist approved for treating moderate‐to‐severe pruritus in adults undergoing hemodialysis (HD). Difelikefalin is not a controlled substance under the Controlled Substances Act. This study assessed the potential for developing physical dependence on difelikefalin in patients undergoing HD. Eligible patients received open‐label difelikefalin after each dialysis session for 3 weeks before entering a 2‐week double‐blind phase, when they were randomized to either continue difelikefalin or to switch to receiving placebo. Signs of physical withdrawal were assessed using the Clinical Opiate Withdrawal Scale (COWS), several patient‐reported scales, and physiological measures. The primary end point was the between‐group difference in mean maximum COWS total scores during the double‐blind phase; the mean difference (placebo − difelikefalin) was compared against a predefined noninferiority limit (+4). Thirty‐five patients (57.1% male; 91.4% Black or African American; median [range] age 58 [28–77] years) were included, of which 30 were randomized (placebo, n = 14; difelikefalin, n = 16). The least squares mean difference in maximum COWS total scores was 0.52 (95% confidence interval [CI]: −0.56, 1.59). The upper CI limit (1.59) was below +4, indicating that patients who discontinued difelikefalin (placebo group) had similar withdrawal scores to patients who continued difelikefalin. Additional assessments supported the COWS results, showing no meaningful differences between groups in physiological measures or in patient‐reported measures of sleep or physical withdrawal. These results demonstrate that abruptly discontinuing chronic difelikefalin treatment in patients undergoing HD does not produce signs or symptoms of physical withdrawal. [ABSTRACT FROM AUTHOR]

Humans have faced poisonous animals since the most ancient times. It is recognized that certain animals, like specific plants, produce toxic substances that can be lethal, but that can also have therapeutic or psychoactive effects. The use of the term "venom", which initially designated a poison, remedy, or magic drug, is now confined to animal poisons delivered by biting. Following Louis Pasteur's work on pathogenic microorganisms, it was hypothesized that venoms could be related to bacterial toxins and that the process of pathogenicity attenuation could be applied to venoms for the prevention and treatment of envenomation. Cesaire Phisalix and Gabriel Bertrand from the National Museum of Natural History as well as Albert Calmette from the Institut Pasteur in Paris were pioneers in the development of antivenomous serotherapy. Gaston Ramon refined the process of venom attenuation for the immunization of horses using a formalin treatment method that was successful for diphtheria and tetanus toxins. This paved the way for the production of antivenomous sera at the Institut Pasteur, as well as for research on venom constituents and the characterization of their biological activities. The specific activities of certain venom components, such as those involved in blood coagulation or the regulation of chloride ion channels, raises the possibility of developing novel therapeutic drugs that could serve as anticoagulants or as a treatment for cystic fibrosis, for example. Scientists of the Institut Pasteur of Paris have significantly contributed to the study of snake venoms, a topic that is reported in this review. [ABSTRACT FROM AUTHOR]

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light–dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects. [ABSTRACT FROM AUTHOR]

Vascular cell adhesion molecule 1 (VCAM-1) plays an important role in tumour cell adhesion to endothelial cells. Some tumour cells also show aberrant expression of VCAM‐1. Toll-like receptor 4 (TLR4) agonists can increase VCAM-1 expression. Morphine, an opioid receptor agonist, is also a TLR4 agonist. In this study, we aimed to evaluate whether morphine increase VCAM-1 expression in a TLR4 dependent manner. A549 Lung cancer cells were treated with different doses of morphine and TLR4 antagonist for 24 and 48 h. TLR4 gene expression was evaluated by real-time PCR and VCAM-1 protein was measured by the enzyme-linked immunosorbent assay (ELISA). Morphine enhanced mRNA expression of TLR4 and protein level of VCAM-1. TLR4 antagonist returned VCAM-1expression to the normal level. Morphine effects VCAM-1expressions via TLR4 in lung cancer cell line. [ABSTRACT FROM AUTHOR]

Salvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms. Mice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A. Sal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI. Sal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs. [Display omitted] • Salvinorin A produced anti-epileptic effect in the pilocarpine-induced model. • Salvinorin A alleviated neuronal damages and inflammation response in the hippocampus of epileptic mice. • Salvinorin A inhibited the polarization of microglia to M1 phenotype and promoted that to M2 phenotype in vivo and in vitro. [ABSTRACT FROM AUTHOR]

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA's suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalA's binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site, we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit with moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and facilitate the development of novel analgesics that are urgently needed. [ABSTRACT FROM AUTHOR]

The article "Manic Episode with Psychotic Features Associated with Salvia divinorum Use: A Case Report" published in the Taiwanese Journal of Psychiatry discusses a case of a 32-year-old male patient who developed a manic episode with psychosis after using Salvia divinorum. The patient had a history of substance use and a family history of bipolar I disorder. Treatment with antipsychotic medication led to a gradual improvement in symptoms, but the patient ultimately died by suicide. The article highlights the potential association between Salvia divinorum use and manic episodes with psychotic features, emphasizing the need for further research and awareness of mental health risks associated with this substance. [Extracted from the article]

The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was prepared from a Wieland‐Miescher ketone using a known γ‐hydroxylation, reduction of the enone double bond, cyanohydrin formation, and elimination, yielding an unsaturated nitrile. A two‐step reduction led to the required allyl alcohol. The subsequent Johnson‐Claisen rearrangement provided a mixture of two diastereomeric 1,4‐unsaturated esters in a ratio of around 2.6 : 1. The major isomer could be converted to a key intermediate of the Hagiwara synthesis of salvinorin A. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a long‐term noncommunicable inflammatory disease of the nasal mucosa mediated by immunoglobulin E and is mainly caused by exposure of genetically susceptible individuals to environmental allergens. Mast cells contribute to the pathogenesis of allergic and nonallergic inflammatory diseases. Salvinorin A has been previously shown to inhibit leukotriene production and mast cell degranulation to suppress airway hyperresponsiveness caused by sensitization; thus, we hypothesized that salvinorin A has an anti‐AR effect. We tested this hypothesis using monoclonal anti‐2,4,6‐dinitrophenyl immunoglobulin E/human serum albumin‐induced rat basophilic leukemia cells (RBL‐2H3 cells) and ovalbumin (OVA)‐induced AR in mice as in vivo and in vitro AR models, respectively. The expression levels of histamine, β‐hexosaminidase, interleukin‐4 and tumor necrosis factor‐α were decreased by salvinorin A in vitro. Granule release and F‐actin organization were also suppressed by salvinorin A. Furthermore, salvinorin A inhibited OVA‐induced features of AR in mice, including nasal rubbing and sneezing, as well as increased OVA‐specific immunoglobulin E, histamine, tumor necrosis factor‐α and interleukin‐4 levels. In addition, salvinorin A decreased the phosphorylation of phosphoinositide 3‐kinase/Akt in vitro and in vivo. Our work suggests that salvinorin A suppresses AR caused by sensitization by inhibiting the inflammatory responses of mast cells; thus, salvinorin A may have potential for treatment of AR.

Abstract The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was prepared from a Wieland‐Miescher ketone using a known γ‐hydroxylation, reduction of the enone double bond, cyanohydrin formation, and elimination, yielding an unsaturated nitrile. A two‐step reduction led to the required allyl alcohol. The subsequent Johnson‐Claisen rearrangement provided a mixture of two diastereomeric 1,4‐unsaturated esters in a ratio of around 2.6 : 1. The major isomer could be converted to a key intermediate of the Hagiwara synthesis of salvinorin A.

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light–dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects.

The continuous emergence of new psychoactive substances (NPS) attracted a great deal of attention within recent years. Lately, the two hallucinogenic NPS 1cP-LSD and 4-AcO-DET have appeared on the global market. Knowledge about their metabolism to identify potential metabolic targets for analysis and their cytotoxic properties is lacking. The aim of this work was thus to study their in vitro and in vivo metabolism in pooled human liver S9 fraction (pHLS9) and in zebrafish larvae (ZL) by means of liquid chromatography-high-resolution tandem mass spectrometry. Monooxygenases involved in the initial metabolic steps were elucidated using recombinant human isozymes. Investigations on their cytotoxicity were performed on the human hepatoma cell line HepG2 using a multiparametric, fluorescence-based high-content screening assay. This included measurement of CYP-enzyme mediated effects by means of the unspecific CYP inhibitor 1-aminbenzotriazole (ABT). Several phase I metabolites of both compounds and two phase II metabolites of 4-AcO-DET were produced in vitro and in vivo. After microinjection of 1cP-LSD into the caudal vein of ZL, three out of seven metabolites formed in pHLS9 were also detected in ZL. Twelve 4-AcO-DET metabolites were identified in ZL after exposure via immersion bath and five of them were found in pHLS9 incubations. Notably, unique metabolites of 4-AcO-DET were only produced by ZL, whereas 1cP-LSD specific metabolites were found both in ZL and in pHLS9. No toxic effects were observed for 1cP-LSD and 4-AcO-DET in HepG2 cells, however, two parameters were altered in incubations containing 4-AcO-DET together with ABT compared with incubations without ABT but in concentrations far above expected in vivo concentration. Further investigations should be done with other hepatic cell lines expressing higher levels of CYP enzymes. • Metabolism of two hallucinogens was compared using the pHLS9 and zebrafish larvae model. • Identification of unique metabolic targets possible for both NPS using the zebrafish larvae model. • Few CYP isoenzymes involved in metabolic steps of 1cP-LSD may be relevant if co-consumed with other drugs (of abuse). • No cytotoxicity in hepatic cells (HepG2) observed for both compounds using a high-content screening assay approach. • Metabolism-based cytotoxicity of 4-AcO-DET cannot be excluded. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa, a species of plant that is native to Thailand, Malaysia and Southeast Asia, contains two major psychoactive alkaloids: mitragynine and 7-hydroxymitragynine. Pharmacologically, the alkaloids exhibit biphasic effects—at low doses, stimulant effects are realized, while high doses exhibit sedative effects. For years, the plant has been used recreationally and medicinally for these effects, but its use has been implicated in and associated with intoxications and deaths. In this case report, we describe two cases whereby decedents presented with single-substance fatal intoxications by mitragynine in the absence of other postmortem toxicological findings. The cases entail young male decedents in outdoor settings (e.g. driving a vehicle and bicycle). Postmortem blood concentrations were 2,325 and 3,809 ng/mL. The medical examiner certified the cause of death as acute mitragynine intoxication in both cases. The toxicology results presented become useful when considering mitragynine to be the offending agent in lethal single-drug intoxications; further, the information included is pertinent to medical examiners, forensic pathologists, forensic toxicologists and emergency department personnel in evaluating possible poisoning and lethality by mitragynine. [ABSTRACT FROM AUTHOR]

Tramadol is a weak mu (µ) opioid receptor agonist that acts by inhibiting serotonin and norepinephrine uptake. Tramadol undergoes extensive hepatic metabolism by a number of pathways, including CYP2D6 and CYP3A4, and by conjugation with subsequent renal excretion. The maximum recommended dose is 400 mg/day. One of the most important adverse effects of tramadol is a seizure, which usually occurs at high doses and is often generalized tonic – clonic type and self-limiting. Here, we present a case of a patient with inflammatory low backache who developed seizures while on low-dose oral tramadol. After 1 h of taking the first tablet of tramadol, he developed morbilliform rashes all over the body. One day later, he developed generalized tonic – clonic seizures followed by a loss of consciousness for 5 min. The patient was admitted to the hospital and managed conservatively with injection lorazepam and tramadol was stopped. In general, if applied in overdose, tramadol can only incite seizures in patients already suffering from some sort of disorder related to seizures or if it is administered along with antidepressants, alcohol, etc. But here, only with the use of 37.5 mg oral application, the incidence of seizure happened. [ABSTRACT FROM AUTHOR]

Salvinorin A (SA), a highly selective kappa opioid receptor agonist, has been shown to reduce brain infarct volume and improve neurological function after ischemic stroke. However, the underlying mechanisms have not been fully understood yet. Therefore, we explored whether SA provides neuroprotective effects by regulating the immune response after ischemic stroke both in the central nervous system (CNS) and peripheral circulation. In this study, adult male mice were subjected to transient Middle Cerebral Artery Occlusion (tMCAO) and then were treated intranasally with SA (50 μg/kg) or with the vehicle dimethyl sulfoxide (DMSO). Multiple behavioral tests were used to evaluate neurofunction. Flow cytometry and immunofluorescence staining were used to evaluate the infiltration of peripheral immune cells into the brain. The tracer cadaverine and endogenous immunoglobulin G (IgG) extravasation were used to detect blood brain barrier leakage. We observed that SA intranasal administration after ischemic stroke decreased the expression of pro-inflammatory factors in the brain. SA promoted the polarization of microglia/macrophages into a transitional phenotype and decreased the pro-inflammatory phenotype in the brain after tMCAO. Interestingly, SA treatment scarcely altered the number of peripheral immune cells but decreased the macrophage and neutrophil infiltration into the brain at 24 h after tMCAO. Furthermore, SA treatment also preserved BBB integrity, reduced long-term brain atrophy and white matter injury, as well as improved the long-term neurofunctional outcome in mice. In this study, intranasal administration of SA improved long-term neurological function via immuno-modulation and by preserving blood–brain barrier integrity in a mouse ischemic stroke model, suggesting that SA could potentially serve as an alternative treatment strategy for ischemic stroke. [ABSTRACT FROM AUTHOR]

Objective To investigate the mechanism of MALAT1-mediated B-catenin pathway involved in Salvinorin A moderates blood brain barrier (BBB) injury after stroke. Methods SD rats were selected to make middle cerebral artery embolization model (MCAO) for the related detection experiment of Salvinorin A alleviating brain injury after stroke. Human microvascular endothelial cells (HBMECs) were selected to make glucose oxygen deprivation (OGD) model, and the relevant experiments on the role of MALAT1-mediated B-catenin pathway in the brain protective mechanism of Salvinorin A were conducted. Results Salvinorin A could significantly reduce the neurological damage, cerebral edema, damage of BBB permeability and endothelial cell injury after ischemia/ reperfusion. However, after MALAT1 interference, the protective effect of Salvinorin A on endothelial cells and the promotion of ß-catenin expression were blocked. Conclusion Salvinorin A may reduce the injury of endothelial cells by regulating the expression of lncRNA-MALAT1 in endothelial cells and promoting the expression of B-catenin, thus alleviating the injury of BBB after ischemia/reperfusion. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance has been posing an alarming threat to the treatment of infectious diseases over the years. Ineffectiveness of the currently available synthetic and semisynthetic antibiotics has led the researchers to discover new molecules with potent antimicrobial activities. To overcome the emerging antimicrobial resistance, new antimicrobial compounds from natural sources might be appropriate. Secondary metabolites from natural sources could be prospective candidates in the development of new antimicrobial agents with high efficacy and less side effects. Among the natural secondary metabolites, diterpenoids are of crucial importance because of their broad spectrum of antimicrobial activity, which has put it in the center of research interest in recent years. The present work is aimed at reviewing recent literature regarding different classes of natural diterpenes and diterpenoids with significant antibacterial, antifungal, antiviral, and antiprotozoal activities along with their reported structure–activity relationships. This review has been carried out with a focus on relevant literature published in the last 5 years following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 229 diterpenoids from various sources like plants, marine species, and fungi are summarized in this systematic review, including their chemical structures, classification, and significant antimicrobial activities together with their reported mechanism of action and structure–activity relationships. The outcomes herein would provide researchers with new insights to find new credible leads and to work on their synthetic and semisynthetic derivatives to develop new antimicrobial agents. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. In the mechanical allodynia testing, U50,488 was more potent in males and SalA was more potent in females. There were no sex differences in the acute cold allodynia testing. In the chronic administration model, treatment with U50,488 (10 mg/kg) reduced the mechanical and cold allodynia responses to healthy levels over 23 days of treatment. Overall, we have shown that KOR agonists are effective in a model of chemotherapy-induced neuropathic pain, indicating that KOR agonists could be further developed to treat this debilitating condition. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. In the mechanical allodynia testing, U50,488 was more potent in males and SalA was more potent in females. There were no sex differences in the acute cold allodynia testing. In the chronic administration model, treatment with U50,488 (10 mg/kg) reduced the mechanical and cold allodynia responses to healthy levels over 23 days of treatment. Overall, we have shown that KOR agonists are effective in a model of chemotherapy-induced neuropathic pain, indicating that KOR agonists could be further developed to treat this debilitating condition.

Vibrational spectroscopy represents a very useful technique that measures the interaction of infrared radiation with materials by absorption, emission, or reflection. It is a very powerful way to investigate and identify chemical compounds or functional groups that exist in solid, liquid, or gaseous forms. It can also be used to characterize and identify chemical compounds. This paper presents the vibrational analysis of some representative 2C-x and DOx hallucinogenic amphetamines. [ABSTRACT FROM AUTHOR]

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site, we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit with moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and facilitate the development of novel analgesics that are urgently needed.

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain. [ABSTRACT FROM AUTHOR]

Rationale: An alarming number of neonates born with prenatal exposure to morphine has resulted from the opioid epidemic; however, the long-term effects of prenatal opioid exposure on offspring behavior remain relatively unknown. In this study, we evaluated whether prenatal exposure to the mu opioid receptor agonist, morphine, has enduring effects on cognitive functions in adult life. Methods: On embryonic days 11–18 (E11-E18), female pregnant rats were injected subcutaneously with either morphine or saline twice daily. Adult male offspring that was prenatally exposed to saline or morphine was trained in the 5-choice serial reaction time test (5-CSRTT) to test their cognitive abilities under baseline conditions. Next, these rats were treated with saline (1 ml/kg), naloxone (1 mg/kg), and acute morphine (1, 3, 5 mg/kg), subcutaneously, once daily and following drug challenges rats were tested in the 5-CSRTT. Meanwhile, behavioral performance on training days between opioid drug challenges were analyzed to monitor possible drug-induced shifts in baseline performance. As a final experiment in order to investigate subchronic exposure to morphine, rats were injected with 5 mg/kg morphine for 5 days and then naloxone in the last day of the experiment (day 6). Results: Firstly, during acquisition of a stable baseline in the training phase, rats prenatally exposed to morphine showed delayed learning of the task demands. Furthermore, under baseline responding the rats prenatally exposed to morphine showed declined inhibitory control demonstrated by increased impulsive and compulsive-like responding compared to rats prenatally exposed to saline. Moreover, acute and subchronic morphine challenges in the rats prenatally exposed to morphine caused a deficit in visuospatial attention in comparison with saline treatment as well as the rats prenatally exposed to saline. These effects were abolished by naloxone. Conclusion: The current findings indicate a direct causal effect of prenatal morphine exposure on inhibitory control and task learning later in life, as well as deficits in attention following morphine exposure in adulthood. [ABSTRACT FROM AUTHOR]

Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a β-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former "legal status", impressive marketing strategies and their commercial availability, either in the so-called "smartshops" or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a long‐term noncommunicable inflammatory disease of the nasal mucosa mediated by immunoglobulin E and is mainly caused by exposure of genetically susceptible individuals to environmental allergens. Mast cells contribute to the pathogenesis of allergic and nonallergic inflammatory diseases. Salvinorin A has been previously shown to inhibit leukotriene production and mast cell degranulation to suppress airway hyperresponsiveness caused by sensitization; thus, we hypothesized that salvinorin A has an anti‐AR effect. We tested this hypothesis using monoclonal anti‐2,4,6‐dinitrophenyl immunoglobulin E/human serum albumin‐induced rat basophilic leukemia cells (RBL‐2H3 cells) and ovalbumin (OVA)‐induced AR in mice as in vivo and in vitro AR models, respectively. The expression levels of histamine, β‐hexosaminidase, interleukin‐4 and tumor necrosis factor‐α were decreased by salvinorin A in vitro. Granule release and F‐actin organization were also suppressed by salvinorin A. Furthermore, salvinorin A inhibited OVA‐induced features of AR in mice, including nasal rubbing and sneezing, as well as increased OVA‐specific immunoglobulin E, histamine, tumor necrosis factor‐α and interleukin‐4 levels. In addition, salvinorin A decreased the phosphorylation of phosphoinositide 3‐kinase/Akt in vitro and in vivo. Our work suggests that salvinorin A suppresses AR caused by sensitization by inhibiting the inflammatory responses of mast cells; thus, salvinorin A may have potential for treatment of AR. [ABSTRACT FROM AUTHOR]

Ulises Coffeen, Francisco Pellicer Research in Neurosciences, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City, México Abstract: Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties. Keywords: Salvia divinorum, salvinorin A, pain, inflammation, psychoactivity

A concise enantioselective total synthesis of the neoclerodane diterpene (−)‐salvinorin A is reported. The stereogenic center at C‐12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels‐Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2‐diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)‐salvinorin A was synthesized in only 16 steps starting from 3‐furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels‐Alder strategy employing a 2‐bromo‐1,3‐diene moiety was investigated. [ABSTRACT FROM AUTHOR]

Salvinorin A (SA) exerts neuroprotection and improves neurological outcomes in ischemic stroke models in rodents. In this study, we investigated whether intranasal SA administration could improve neurological outcomes in a monkey ischemic stroke model. The stroke model was induced in adult male rhesus monkeys by occluding the middle cerebral artery M2 segment with an autologous blood clot. Eight adult rhesus monkeys were randomly administered SA or 10% dimethyl sulfoxide as control 20 min after ischemia. Magnetic resonance imaging was used to confirm the ischemia and extent of injury. Neurological function was evaluated using the Non-Human Primate Stroke Scale (NHPSS) over a 28-day observation period. SA significantly reduced infarct volume (3.9 ± 0.7 cm3 vs. 7.2 ± 1.0 cm3; P = 0.002), occupying effect (0.3 ± 0.2% vs. 1.4 ± 0.3%; P = 0.002), and diffusion limitation in the lesion (−28.2 ± 11.0% vs. −51.5 ± 7.1%; P = 0.012) when compared to the control group. SA significantly reduced the NHPSS scores to almost normal in a 28-day observation period as compared to the control group (P = 0.005). Intranasal SA reduces infarct volume and improves neurological outcomes in a rhesus monkey ischemic stroke model using autologous blood clot. [ABSTRACT FROM AUTHOR]

In the search for safer, non-addictive analgesics, kappa opioid receptor (KOPr) agonists are a potential target, as unlike mu-opioid analgesics, they do not have abuse potential. Salvinorin A (SalA) is a potent and selective KOPr agonist, however, clinical utility is limited by the short duration of action and aversive side effects. Biasing KOPr signaling toward G-protein activation has been highlighted as a key cellular mechanism to reduce the side effects of KOPr agonists. The present study investigated KOPr signaling bias and the acute antinociceptive effects and side effects of two novel analogs of SalA, 16-Bromo SalA and 16-Ethynyl SalA. 16-Bromo SalA showed G-protein signaling bias, whereas 16-Ethynyl SalA displayed balanced signaling properties. In the dose-response tail-withdrawal assay, SalA, 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail-withdrawal assay, and 16-Ethynyl had greater antinociceptive effect in the hot-plate assay, compared to SalA. In the intraplantar 2% formaldehyde test, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced both nociceptive and inflammatory pain-related behaviors. Moreover, 16-Ethynyl SalA and 16-Bromo SalA had no anxiogenic effects in the marble burying task, and 16-Bromo SalA did not alter behavior in the elevated zero maze. Overall, 16-Ethynyl SalA significantly attenuated acute pain-related behaviors in multiple preclinical models, while the biased KOPr agonist, 16-Bromo SalA, displayed modest antinociceptive effects, and lacked anxiogenic effects.

The drug market has seen a significant global expansion in the last decades. The synthetic designer drugs belonging to the class of amphetamines and derived phenylethylamines have experienced the greatest spread in the drug market for abuse. As phenylethylamines are organic compounds that stimulate the central nervous system of humans, many are abused as recreational drugs. A large array of substituted amphetamines can be easily synthetized by replacing one or more hydrogen atoms in the structure of phenylethylamine. Among these, the most dangerous for human health are those analogues or homologues that have hallucinogenic effects (besides the stimulant pharmacological activity), such as those belonging to the 2C-x and DOx classes of amphetamines. This review describes the physico-chemical and spectral properties of the most representative compounds of the two classes. [ABSTRACT FROM AUTHOR]

The aim of this work was to investigate the applicability of a mathematical model developed for the description of supercritical fluid extraction (SFE) of cannabinoids from marijuana and hashish for liquid extraction of other substances. The mentioned model is applicable for dynamic SFE whose implementation is analogous to liquid–solid extraction in quasi-counter current mode. According to this model, quasi-counter current liquid–solid extractions were designed by calculation of component transport constants for extractions of psilocin from hallucinogenic mushroom, mescaline from hallucinogenic cactus, harmine from tropical lyan and salvinorin A from hallucinogenic sage. The mentioned model was found to be suitable for the determination of extraction time needed to reach a predefined extraction recovery for quasi-counter current liquid–solid extractions, as well, which allows the elimination of systematic error caused by the non-extracted part. The calculated component transport constants predict the expectable velocity of the extraction, i.e. the higher the component transport constant is, the higher the extraction velocity is. For mushrooms, it could be stated that preliminary treatment of mushrooms with liquid nitrogen significantly increases the extractability of psilocin. [ABSTRACT FROM AUTHOR]

Covering: 2000 to 2020 The hallucinogenic diterpene salvinorin A potently and selectively agonizes the human kappa-opioid receptor (KOR). Its unique attributes-lack of a basic nitrogen, rapid brain penetrance, short half-life-combined with the potential of KOR as an emerging target for analgesics have stimulated extensive medicinal chemistry based on semi-synthesis from extracts of Salvia divinorum. Total synthesis efforts have delivered multiple, orthogonal routes to salvinorin A, its congeners and related analogs with the goal of optimizing its activity towards multiple functional endpoints. Here we review total syntheses of the salvinorin chemotype and discuss outstanding problems that synthesis can address in the future. [ABSTRACT FROM AUTHOR]

Background and Objective: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective μ-agonist with limited activity on β-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. Methods: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. Results: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. Conclusion: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation. [ABSTRACT FROM AUTHOR]

In the search for safer, non-addictive analgesics, kappa opioid receptor (KOPr) agonists are a potential target, as unlike mu-opioid analgesics, they do not have abuse potential. Salvinorin A (SalA) is a potent and selective KOPr agonist, however, clinical utility is limited by the short duration of action and aversive side effects. Biasing KOPr signaling toward G-protein activation has been highlighted as a key cellular mechanism to reduce the side effects of KOPr agonists. The present study investigated KOPr signaling bias and the acute antinociceptive effects and side effects of two novel analogs of SalA, 16-Bromo SalA and 16-Ethynyl SalA. 16-Bromo SalA showed G-protein signaling bias, whereas 16-Ethynyl SalA displayed balanced signaling properties. In the dose-response tail-withdrawal assay, SalA, 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail-withdrawal assay, and 16-Ethynyl had greater antinociceptive effect in the hot-plate assay, compared to SalA. In the intraplantar 2% formaldehyde test, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced both nociceptive and inflammatory pain-related behaviors. Moreover, 16-Ethynyl SalA and 16-Bromo SalA had no anxiogenic effects in the marble burying task, and 16-Bromo SalA did not alter behavior in the elevated zero maze. Overall, 16-Ethynyl SalA significantly attenuated acute pain-related behaviors in multiple preclinical models, while the biased KOPr agonist, 16-Bromo SalA, displayed modest antinociceptive effects, and lacked anxiogenic effects. [ABSTRACT FROM AUTHOR]