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The novel NHC ligand precursor 1,4-bis(4-nitrobenzyl)-1H-1,2,4-triazol-4-ium bromide, [HTz(pNO2Bz)2]Br, has been synthesized and used in the synthesis of the corresponding metal complexes M[Tz(pNO2Bz)2]Br (M = Cu(i), Ag(i) or Au(i)). These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. The complete series of Au(i), Ag(i) and Cu(i) 1,2,4-triazole based NHC complexes has been synthesized aiming at a SAR study and at identifying the primary cellular targets accounting for their cytotoxic action. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin sensitive and resistant cells, the most efficacious antiproliferative compound being Cu(i)–NHC, which was able to promote a growth inhibitory effect up to ten times higher than that promoted by cisplatin. A detailed analysis of molecular and cellular pharmacology allowed us to elucidate the role of the metallic core in determining the biological properties. In particular, gold(i) and silver(i) NHC complexes were found to be able to hamper mammalian thioredoxin reductase (TrxR) activity in human A431 cervical cancer cells, ultimately leading to a dramatic alteration of the cellular redox state and to the induction of cell death via apoptosis. Conversely, the copper NHC complex was found to be capable of inhibiting proteasome functionality thus determining the induction of a non-apoptotic cell death pathway. [ABSTRACT FROM AUTHOR]

5-HT1A receptor (5-HT1A-R) is a serotoninergic G-protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5-HT-R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure-activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5-HT1A-R selective/preferential ligands; (ii) identification of 5-HT1A-R biased agonists, differentiating pre- versus post-synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well-defined poly-pharmacological profiles targeting 5-HT1A-R along with other serotonin receptors, serotonin transporter (SERT), D2-like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5-HT1A-R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017-2023) have been discussed. The development of chemical and pharmacological 5-HT1A-R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5-HT1A-R and the therapeutic potential of ligands targeting this receptor have been considered., (© 2024 Wiley Periodicals LLC.)

A new series of muscarinic acetylcholine receptor (mAChR) ligands obtained by inserting different substituents in position 2 of the potent 6,6-diphenyl-1,4-dioxane antagonists 4 and 5 was designed and synthesized to investigate the influence of steric bulk on the mAChR affinity. Specifically, the insertion of a 2-methyl group, affording compounds 6 and 9, resulted as the most favorable modification in terms of affinity for all muscarinic subtypes. As supported by computational studies performed on the hM 1 receptor, this substituent may contribute to stabilize the ligand within the binding site by favoring the formation of stable interactions between the cationic head of the ligand and the residue D105. The increase of steric bulk, obtained by replacing the methyl group with an ethyl (7 and 10) and especially a phenyl substituent (8 and 11), caused a marked decrease of mAChR affinity, demonstrating the crucial role played by the steric bulk of the 2-substituent in the mAChR interaction. The most intriguing result was obtained with the tertiary amine 9, which, surprisingly, showed two different pK i values for all mAChRs, with preferential subpicomolar affinities for the M 1 , M 3 , and M 4 subtypes. Interestingly, biphasic curves were also observed with both the eutomer (S)-(-)-9 and the distomer (R)-( + )-9., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

One interesting field of research in the view of developing novel surfactants for pharmaceutical and cosmetic applications is the design of amphiphiles showing further bioactive properties in addition to those commonly displayed by surface-active compounds. We propose here the chemical synthesis, and characterization of 1-o-tolyl alkyl biguanide derivatives, having different lengths of the hydrocarbon chain (C3, C6, and C10), and showing surface active and antibacterial/disinfectant activities toward both Gram-positive and Gram-negative bacteria. Both surface active properties in terms of critical micelle concentration (CMC) and surface tension at CMC (γCMC), as well as the antimicrobial activity in terms of minimum inhibitory concentrations (MICs), were strongly dependent on the length of the hydrocarbon chain. Particularly, the C6 and C10 derivatives have a good ability to decrease surface tension (γCMC <40 mN/m) at low concentrations (CMC < 12 mM) and a satisfactory antibacterial effect (MIC values between 0.230 and 0.012 mM against S. aureus strains and between 0.910 and 0.190 against P.aeruginosa strains). Interestingly, these compounds showed a disinfectant activity at the tested concentrations that was comparable to that of the reference compound chlorhexidine digluconate. All these results support the possible use of these amphiphilic compounds as antibacterial agents and disinfectants in pharmaceutical or cosmetic formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In the framework of the design, synthesis and testing of a library of copper complexes and nanostructured assemblies potentially endowed with antitumor and antiviral activity and useful for several applications, from drugs and related delivery systems to the development of biocidal nanomaterials, we present the detailed spectroscopic investigation of the molecular and electronic structure of copper-based coordination compounds and of a new conjugated system obtained by grafting Cu(I) complexes to gold nanorods. More in detail, the electronic and molecular structures of two Cu complexes and one AuNRs/Cu-complex adduct were investigated by X-ray photoelectron spectroscopy (XPS), synchrotron-induced XPS (SR-XPS) and near edge X-ray absorption spectroscopy (NEXAFS) in solid state, and the local structure around copper ion was assessed by X-ray absorption spectroscopy (XAS) both in solid state and water solution for the AuNRs/Cu-complex nanoparticles. The proposed multi-technique approach allowed to properly define the coordination geometry around the copper ion, as well as to ascertain the molecular structures of the coordination compounds, their stability and modifications upon interaction with gold nanoparticles, by comparing solid state and liquid phase data., (© 2024 Wiley-VCH GmbH.)

The new ligand L 2Ad , obtained by conjugating the bifunctional species bis(3,5-dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of new Cu complexes 1 - 5 . Their structures were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and by combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modeling. The structure of complex 3 was determined by single-crystal X-ray diffraction analysis. Tested on U87, T98, and U251 glioma cells, Cu(II) complex 3 and Cu(I) complex 5 decreased cell viability with IC 50 values significantly lower than cisplatin, affecting cell growth, proliferation, and death. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their cytotoxic activity. Both complexes were able to increase ROS production, leading to DNA damage and death. Interestingly, nontoxic doses of 3 or 5 enhanced the chemosensitivity to Temozolomide.

Nicotinamide adenine dinucleotide (NAD) cofactor metabolism plays a significant role in cancer development. Tumor cells have an increased demand for NAD and ATP to support rapid growth and proliferation. Limiting the amount of available NAD by targeting critical NAD biosynthesis enzymes has emerged as a promising anticancer therapeutic approach. In mammals, the enzyme nicotinamide/nicotinic acid adenylyltransferase (NMNAT) catalyzes a crucial downstream reaction for all known NAD synthesis routes. Novel nicotinamide/nicotinic acid adenine dinucleotide (NAD/NaAD) analogues 1 - 4 , containing a methyl group at the ribose 2'- C and 3'- C -position of the adenosine moiety, were synthesized as inhibitors of the three isoforms of human NMN-adenylyltransferase, named h NMNAT-1, h NMNAT-2, and h NMNAT-3. An NMR-based conformational analysis suggests that individual NAD-analogues ( 1 - 4 ) have distinct conformational preferences. Biological evaluation of dinucleotides 1 - 4 as inhibitors of h NMNAT isoforms revealed structural relationships between different conformations (North- anti and South- syn ) and enzyme-inhibitory activity. Among the new series of NAD analogues synthesized and tested, the 2'- C -methyl-NAD analogue 1 ( K i = 15 and 21 µM towards NMN and ATP, respectively) emerged as the most potent and selective inhibitor of h NMNAT-2 reported so far. Finally, we rationalized the in vitro bioactivity and selectivity of methylated NAD analogues with in silico studies, helping to lay the groundwork for rational scaffold optimization.

Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered., (© 2023 Wiley Periodicals LLC.)

Neuromedin U (NMU) is a bioactive peptide produced in the gut and in the brain, with a role in multiple physiological processes. NMU acts by binding and activating two G protein coupled receptors (GPCR), the NMU receptor 1 (NMU-R1), which is predominantly expressed in the periphery, and the NMU receptor 2 (NMU-R2), mainly expressed in the central nervous system (CNS). In the brain, NMU and NMU-R2 are consistently present in the hypothalamus, commonly recognized as the main "feeding center". Considering its distribution pattern, NMU revealed to be an important neuropeptide involved in the regulation of food intake, with a powerful anorexigenic ability. This has been observed through direct administration of NMU and by studies using genetically modified animals, which revealed an obesity phenotype when the NMU gene is deleted. Thus, the development of NMU analogs or NMU-R2 agonists might represent a promising pharmacological strategy to treat obese individuals. Furthermore, NMU has been demonstrated to influence the non-homeostatic aspect of food intake, playing a potential role in binge eating behavior. This review aims to discuss and summarize the current literature linking the NMU system with obesity and binge eating behavior, focusing on the influence of NMU on food intake and the neuronal mechanisms underlying its anti-obesity properties. Pharmacological strategies to improve the pharmacokinetic profile of NMU will also be reported., Competing Interests: Declaration of Competing Interest All authors declare that there are no conflicts of interest associated with the content of this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prevention of nicotinamide adenine dinucleotide (NAD) biosynthesis is considered an attractive therapeutic approach against cancer, considering that tumor cells are characterized by an increased need for NAD to fuel their reprogrammed metabolism. On the other hand, the decline of NAD is a hallmark of some pathological conditions, including neurodegeneration and metabolic diseases, and boosting NAD biosynthesis has proven to be of therapeutic relevance. Therefore, targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD biosynthesis from nicotinamide (NAM) and nicotinic acid (NA), respectively, is considered a promising strategy to modulate intracellular NAD pool. While potent NAMPT inhibitors and activators have been developed, the search for NAPRT modulators is still in its infancy. In this work, we report on the identification of a new class of NAPRT modulators bearing the 1,2-dimethylbenzimidazole scaffold properly substituted in position 5. In particular, compounds 24 , 31 , and 32 emerged as the first NAPRT activators reported so far, while 18 behaved as a noncompetitive inhibitor toward NA ( K i = 338 µM) and a mixed inhibitor toward phosphoribosyl pyrophosphate (PRPP) ( K i = 134 µM). From in vitro pharmacokinetic studies, compound 18 showed an overall good ADME profile. To rationalize the obtained results, docking studies were performed on the NAPRT structure. Moreover, a preliminary pharmacophore model was built to shed light on the shift from inhibitors to activators.

The maintenance of a proper NAD + pool is essential for cell survival, and tumor cells are particularly sensitive to changes in coenzyme levels. In this view, the inhibition of NAD + biosynthesis is considered a promising therapeutic approach. Current research is mostly focused on targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD + biosynthesis from nicotinamide and nicotinic acid, respectively. In several types of cancer cells, both enzymes are relevant for NAD + biosynthesis, with NAPRT being responsible for cell resistance to NAMPT inhibition. While potent NAMPT inhibitors have been developed, only a few weak NAPRT inhibitors have been identified so far, essentially due to the lack of an easy and fast screening assay. Here we present a continuous coupled fluorometric assay whereby the product of the NAPRT-catalyzed reaction is enzymatically converted to NADH, and NADH formation is measured fluorometrically. The assay can be adapted to screen compounds that interfere with NADH excitation and emission wavelengths by coupling NADH formation to the cycling reduction of resazurin to resorufin, which is monitored at longer wavelengths. The assay system was validated by confirming the inhibitory effect of some NA-related compounds on purified human recombinant NAPRT. In particular, 2-hydroxynicotinic acid, 2-amminonicotinic acid, 2-fluoronicotinic acid, pyrazine-2-carboxylic acid, and salicylic acid were confirmed as NAPRT inhibitors, with Ki ranging from 149 to 348 µM. Both 2-hydroxynicotinic acid and pyrazine-2-carboxylic acid were found to sensitize OVCAR-5 cells to the NAMPT inhibitor FK866 by decreasing viability and intracellular NAD + levels.

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress., Competing Interests: Conflict of interest All authors declare that there are no conflicts of interest associated with the content of this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To better understand the role of dopamine D 4 receptor (D 4 R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D 4 R were discovered starting from the brain penetrant and D 4 R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1 H )-one ( 6 ). In particular, the D 4 R antagonist 24 , showing the highest affinity and selectivity over D 2 R and D 3 R within the series (D 2 /D 4 = 8318, D 3 /D 4 = 3715), and the biased ligand 29 , partially activating D 4 R G i -/G o -protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds 24 and 29 induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.

Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh 3 -containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

In the search for novel bitopic compounds targeting the dopamine D 3 receptor (D 3 R), the N -(2,3-dichlorophenyl)piperazine nucleus (primary pharmacophore) has been linked to the 6,6- or 5,5-diphenyl-1,4-dioxane-2-carboxamide or the 1,4-benzodioxane-2-carboxamide scaffold (secondary pharmacophore) by an unsubstituted or 3-F-/3-OH-substituted butyl chain. This scaffold hybridization strategy led to the discovery of potent D 3 R-selective or multitarget ligands potentially useful for central nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane derivative 3 showed a D 3 R-preferential profile, while an interesting multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9 , respectively, which displayed potent D 2 R antagonism, 5-HT 1A R and D 4 R agonism, as well as potent D 3 R partial agonism. They also behaved as low-potency 5-HT 2A R antagonists and 5-HT 2C R partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents.

The peripheral peptide hormone ghrelin is a powerful stimulator of food intake, which leads to body weight gain and adiposity in both rodents and humans. The hormone, thus, increases the vulnerability to obesity and binge eating behavior. Several studies have revealed that ghrelin's functions are due to its interaction with the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamic area; besides, ghrelin also promotes the reinforcing properties of hedonic food, acting at extra-hypothalamic sites and interacting with dopaminergic, cannabinoid, opioid, and orexin signaling. The hormone is primarily present in two forms in the plasma and the enzyme ghrelin O-acyltransferase (GOAT) allows the acylation reaction which causes the transformation of des-acyl-ghrelin (DAG) to the active form acyl-ghrelin (AG). DAG has been demonstrated to show antagonist properties; it is metabolically active, and counteracts the effects of AG on glucose metabolism and lipolysis, and reduces food consumption, body weight, and hedonic feeding response. Both peptides seem to influence the hypothalamic-pituitary-adrenal (HPA) axis and the corticosterone/cortisol level that drive the urge to eat under stressful conditions. These findings suggest that DAG and inhibition of GOAT may be targets for obesity and bingeing-related eating disorders and that AG/DAG ratio may be an important potential biomarker to assess the risk of developing maladaptive eating behaviors., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cancer chemotherapy can significantly impair the bone formation and cause myelosuppression; however, their recovery potentials and mechanisms remain unclear. This study investigated the roles of the β-catenin signaling pathway in bone and bone marrow recovery potentials in rats treated with antimetabolite methotrexate (MTX) (five once-daily injections, 0.75 mg/kg) with/without β-catenin inhibitor indocyanine green (ICG)-001 (oral, 200 mg/kg/day). ICG alone reduced trabecular bone volume and bone marrow cellularity. In MTX-treated rats, ICG suppressed bone volume recovery on Day 11 after the first MTX injection. ICG exacerbated MTX-induced decreases on Day 9 osteoblast numbers on bone surfaces, their formation in vitro from bone marrow stromal cells (osteogenic differentiation/mineralization), as well as expression of osteogenesis-related markers Runx2, Osx, and OCN in bone, and it suppressed their subsequent recoveries on Day 11. On the other hand, ICG did not affect MTX-induced increased osteoclast density and the level of the osteoclastogenic signal (RANKL/OPG expression ratio) in bone, suggesting that ICG inhibition of β-catenin does nothing to abate the increased bone resorption induced by MTX. ICG also attenuated bone marrow cellularity recovery on Day 11, which was associated with the suppressed recovery of CD34 + or c-Kit +  hematopoietic progenitor cell contents. Thus, β-catenin signaling is important for osteogenesis and hematopoiesis recoveries following MTX chemotherapy., (© 2020 Wiley Periodicals LLC.)

Since its discovery, the dopamine D 4 receptor (D 4 R) has been suggested to be an attractive target for the treatment of neuropsychiatric diseases. Novel findings have renewed the interest in such a receptor as an emerging target for the management of different diseases, including cancer, Parkinson's disease, alcohol or substance use disorders, eating disorders, erectile dysfunction and cognitive deficits. The recently resolved crystal structures of D 4 R in complexes with the potent ligands nemonapride and L-745870 strongly improved the knowledge on the molecular mechanisms involving the D 4 R functions and may help medicinal chemists in drug design. This review is focused on the recent development of the subtype selective D 4 R ligands belonging to classical or new chemotypes. Moreover, ligands showing functional selectivity toward G protein activation or β-arrestin recruitment and the effects of selective D 4 R ligands on the above-mentioned diseases are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The ocular drug discovery arena has undergone a significant improvement in the last few years culminating in the FDA approvals of 8 new drugs. However, despite a large number of drugs, generics, and combination products available, it remains an urgent need to find breakthrough strategies and therapies for tackling ocular diseases. Targeting the adenosinergic system may represent an innovative strategy for discovering new ocular therapeutics. This review focused on the recent advance in the field and described the numerous nucleoside and non-nucleoside modulators of the four adenosine receptors (ARs) used as potential tools or clinical drug candidates., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021.)

The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years.

In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ 1 ) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3 . To evaluate the effect of the increase in the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at the σ 1 receptor significantly higher than that of the lead compound 1 . In particular, 3 displayed unprecedented selectivity over the σ 2 receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over the dopamine transporter. Docking results supported the structure-activity relationship studies. Due to its interesting biological profile, derivative 3 , selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of the σ 1 receptor in the compulsive-like eating behavior and supported the σ 1 receptor as a promising target for the management of eating disorders.

The dopamine D4 receptor (DRD4) has a predominant expression in the prefrontal cortex (PFC), brain area strictly involved in the modulation of reward processes related to both food and drug consumption. Additionally, the human DRD4 gene is characterized by a variable number of tandem repeats (VNTR) in the exon 3 and, among the polymorphic variants, the 7-repeat (7R) allele appears as a contributing factor in the neurobiological mechanisms underlying drug abuse, aberrant eating behaviors and related comorbidities. The 7R variant encodes for a receptor with a blunted intracellular response to dopamine, and carriers of this polymorphism might be more tempted to enhance dopamine levels in the brain, through the overconsumption of drugs of abuse or palatable food, considering their reinforcing properties. Moreover, the presence of this polymorphism seems to increase the susceptibility of individuals to engage maladaptive eating patterns in response to negative environmental stimuli. This review is focused on the role of DRD4 and DRD4 genetic polymorphism in these neuropsychiatric disorders in both clinical and preclinical studies. However, further research is needed to better clarify the complex DRD4 role, by using validated preclinical models and novel compounds more selective for DRD4.

Anti-cancer therapy based on the repeated administration of oxaliplatin is limited by the development of a disabling neuropathic syndrome with detrimental effects on the patient's quality of life. The lack of effective pharmacological approaches calls for the identification of innovative therapeutic strategies based on new targets. We focused our attention on the imidazoline I 1 receptor (I 1 -R) and in particular on the selective I 1 -R agonist 2-(1-([1,1'-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline). The purpose of this work was the preclinical evaluation of the efficacy of carbophenyline on oxaliplatin-induced neuropathic pain in mice. Carbophenyline, acutely per os administered (0.1-10 mg kg -1 ), induced a dose-dependent anti-hyperalgesic effect that was completely blocked by the pre-treatment with the I 1 -R antagonist 3 or the I 1 /α 2 receptor antagonist efaroxan, confirming the I 1 -R-dependent mechanism. Conversely, pre-treatment with the I 2 -R antagonist BU224 did not block the anti-nociceptive effect evoked by carbophenyline. Repeated oral administrations of carbophenyline (1 mg kg -1 ) for 14 days, starting from the first day of oxaliplatin injection, counteracted the development of neuropathic pain in all behavioral tests (cold plate, Von Frey, and paw pressure tests) carried out 24 h after the last carbophenyline treatment on days 7 and 14. In the dorsal horn of the spinal cord, carbophenyline significantly decreased the oxaliplatin-induced astrocyte activation detected by immunofluorescence staining by the specific labelling with GFAP antibody. In conclusion, carbophenyline showed anti-neuropathic properties both after acute and chronic treatment with preventive effect against oxaliplatin-induced astrocyte activation in the spinal cord. Therefore, I 1 -R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain.

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M 1 -M 5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b , with a cis configuration between the CH 2 N + (CH 3 ) 3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed p K i values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2 S ,6 S )-(-)- 3b and (2 S ,6 S )-(-)- 33b , respectively. Docking simulations on the M 3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M 3 /M 2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M 3 receptors are involved.

In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L 2 H), and bis(pyrazol-1-yl) acetates conjugated with an N -methyl-d-aspartate (NMDA) receptor antagonist (L NMDA or L 2NMDA ) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L 2 H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concentration (IC 50 ) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphological analysis revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.

The enantiomers of the potent σ 1 receptor antagonist (±)- 1 were synthesized and evaluated for their affinity at σ 1 , σ 2 receptors and dopamine transporter (DAT). Analogously to (±)- 1 , both of the enantiomers showed very high affinity for the σ 1 receptor and unprecedented selectivity over both the σ 2 receptor and DAT. The lack of enantioselectivity between ( + )- 1 and (-)- 1 indicated that the center of chirality in the 2-position of the benzothiochromane nucleus does not play a crucial role in the interaction with any of the studied targets. Docking studies confirmed that the configuration of the enantiomers has only marginal effects on the molecular interactions with the σ 1 receptor. In in vivo studies in a female rat model of binge eating, (±)- 1 dose-dependently decreased the binge eating episode elicited by a history of intermittent food restriction and stress, confirming and strengthening the important role played by the σ 1 receptor in bingeing-related eating disorders.

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT 1A R and α 1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT 1A R (pKi 5-HT 1A  = 8.8; pD 2  = 9.22, %E max  = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D 2 -like, 5-HT 1A , and α 1 -adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT 1A /D 4 agonism and D 2 /D 3 /5-HT 2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D 2 and as a potent full agonist at D 3 and D 4 subtypes. In addition to its potent 5-HT 1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT 1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

A series of derivatives obtained by moving the aromatic moiety on the 1,4-dioxane ring of compounds 1-3 from position 6 to position 2 or 3 was prepared and evaluated for the affinity for 5-HT 1A receptor (5-HT 1A R) and α 1 -adrenoceptor (α 1 -AR) subtypes. Moreover, the flexible 2-ethanolamine linker of the most interesting compounds was replaced by the more conformationally constrained piperazine ring. In vitro functional studies performed on derivatives showing the highest affinities for 5-HT 1A R highlighted that the shifting of the diphenyl moiety of derivatives 2 and 13 from position 6 to position 3 of the 1,4-dioxane nucleus, affording 11 and 16, respectively, modulated the 5-HT 1A R functional profile from agonism to antagonism. Docking simulations, performed on the human 5-HT 1A R, further rationalized the biological results, delving into the features which modulate the shift between agonist and antagonist activity. Interestingly, compound 11, endowed with mixed 5-HT 1A R/α 1d -AR antagonist profile, showed antiproliferative and cytotoxic effects on both PC-3 and DU-145 prostate cancer cell lines higher than those of the α 1d -AR antagonist 2 and the 5-HT 1A R antagonist 16. The experiments performed in the presence of the endogenous agonists norepinephrine and serotonin confirmed the involvement of both receptor systems in the antitumor activity of 11., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). However, although it represents the "gold standard" of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects., Competing Interests: The authors declare no conflict of interest.

The potent N -methyl-d-aspartate (NMDA) receptor antagonists 1 - 3 have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast cancer cell lines. To improve the knowledge about the role played by the NMDA receptor in the antitumor activity of these compounds, the enantiomers of 1 were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA receptor. The ( S )- 1 enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of ( R )- 1 , which instead bound the PCP site. The downregulation of NMDA GluN1 expression resulted in a decreased ( S )- 1 -induced cytotoxicity and apoptotic cell death, unequivocally demonstrating the involvement of the NMDA receptor in the antitumor effect of this compound. Due to its interesting biological profile, ( S )- 1 represents a lead compound to develop novel antitumor agents for breast cancer treatment., Competing Interests: The authors declare no competing financial interest.

In the present article, the M 1 mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D 4 R selectivity over D 2 R and D 3 R and to behave as a D 4 R antagonist. To better understand the structural features required for the selective interaction with the D 4 R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D 4 R affinity and selectivity not only over the other D 2 -like subtypes, but also over M 1 -M 5 mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating G i protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D 4 R in disorders in which this subtype is involved.

Within the research field of antitumor metal-based agents alternative to platinum drugs, gold(I/III) coordination complexes have always been in the forefront due mainly to the familiarity of medicinal chemists with gold compounds, whose application in medicine goes back in the ancient times, and to the rich chemistry shown by this metal. In the last decade, N-heterocyclic carbene ligands (NHC), a class of ligands that largely resembles the chemical properties of phosphines, became of interest for gold(I) medicinal applications, and since then, the research on NHC-gold(I/III) coordination complexes as potential antiproliferative agents boosted dramatically. Different classes of gold(I/III)-NHC complexes often showed an outstanding in vitro antiproliferative activity, however up to now very few in vivo data have been reported to corroborate the in vitro results. This review summarizes all achievements in the field of gold (I/III) complexes comprising NHC ligands proposed as potential antiproliferative agents in the period 2004-2016, and critically analyses biological data (mainly IC 50 values) in relation to the chemical structures of Au compounds. The state of art of the in vivo studies so far described is also reported., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)