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In the text, the synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilide derivatives of amino acids are described. They have shown inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, also including glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

The synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilidine derivatives of aminoacids have been described. They showed inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range and as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070 also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as components of Schiff base ligand, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models, in general. Moreover, the most of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathway in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all above models, including also glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion has put forward explications for the results within the wider scope of the knowledge about vanadium complexes.

Many studies involving compounds that enhance histamine release, such as histamine H

Background Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity. Methods Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation. Results Selected results for KM-408: Ki sigma = 7.2*10–8; Ki 5-HT1A = 8.0*10–7; ED50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)—active at 30 mg/kg; SNL (rats, ip)—active at 6 mg/kg; STZ-induced pain (mice, ip)—active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)—active at 30 mg/kg; ED50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)—active at 0.5%; corneal anesthesia (guinea pigs)—active at 0.125%; infiltration anesthesia (guinea pigs)—active at 0.125%. Conclusions Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment. Graphical abstract

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D

Small drug-like molecules that can block the function of serotonin 5-HT

GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation, however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K+ channels. PSB-KD-107 may affect blood pressure and heart function after a single administration, however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation—an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia—an impairment of cardiac rhythm due to cardiac ion channel dysfunction—is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

Background Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. Methods Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model. Results Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3 μM) being more active than sarpogrelate (IC50 = 66.8 μM) and comparable with ketanserin (IC50 = 32.1 μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. Conclusions Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT1A, α2-receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na+ currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy.

Small drug-like molecules that can block the function of serotonin 5-HT2A receptors have garnered considerable attention due to their ability to inhibit platelet aggregation and the possible prevention of atherosclerotic lesions. Although clinical data provided compelling evidence for the efficacy of this approach in the prevention of various cardiovascular conditions, the chemical space of 5-HT2A receptor antagonists is limited to ketanserin and sarpogrelate. To expand the portfolio of novel chemical motifs with potential antiplatelet activity, we evaluated the antiplatelet activity of a series of 6-fluorobenzo[d]isoxazole derivatives that possess a high affinity for 5-HT2A receptor. Here we describe in vitro studies showing that 6-fluorobenzo[d]isoxazole derivatives exert promising antiplatelet activity in three various in vitro models of platelet aggregation, as well as limit serotonin-induced vasoconstriction. Compound AZ928 showed in vitro activity greater than the clinically approved drug sarpogrelate. In addition to promising antiplatelet activity, the novel series was characterized by a favorable safety profile. Our findings show that the novel series exerts promising antiplatelet efficacy while being deprived of potential side effects, such as hemolytic activity, which render these compounds as potential substances for further investigation in the field of cardiovascular research.

Background and aims Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K+ pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used. Methods and results Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects. Conclusions α1–adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α1-blockers may be an interesting option for treatment of hypertension with metabolic complications.

We investigated the therapeutic effect of MH-76 and MH-79, which are non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/K + pathway, on deoxycorticosterone acetate (DOCA)-salt induced hypertension in rats. Prazosin was used as a reference compound, as quinazoline-based α1-adrenolytics may potentially exert unfavorable proapoptotic and necrotic effects. DOCA-salt hypertension was induced by DOCA (20 mg/kg s.c., twice weekly) administration plus 1% NaCl and 0.2% KCl solutions in drinking water for 12 weeks. The studied compounds MH-76, MH-79 (10 mg/kg i.p.) or prazosin (0.4 mg/kg i.p.) were administered to the DOCA-salt-treated rats, starting from the 6th week of DOCA-salt treatment and continuing for 6 weeks. This study showed that the administration of MH-79 and, to a lesser extent, MH-76 decreased elevated systolic blood pressure and heart rate, reduced heart and kidney hypertrophy, and reversed the histopathological alterations of the heart, kidney, and vessels in DOCA-salt hypertensive rats. MH-79 reversed endothelial dysfunction, which reduced inflammatory cell infiltration, arteriosclerotic alterations in renal and coronary arteries, and tubulointerstitial fibrosis. Prazosin showed a potent hemodynamic effect and reduced cardiac and renal fibrosis but exerted detrimental effects on blood vessels, potentiating fibroplasia of the media of the intrarenal artery and causing calcification of coronary arteries. Prazosin did not reverse endothelial dysfunction. Our results show the beneficial effect of non-quinazoline α1-adrenolytics on cardiac, vascular, and renal dysfunction in DOCA-salt hypertensive rats. Our findings also support the idea that targeting endothelial protection and endothelial integrity would yield beneficial effects against cardiac, blood vessel and renal injury related to hypertension.

Background: Quinazoline α1-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes, however, these effects were proven to be independent of α1-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.

Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline αMale rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects.α

A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1'-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HTIA, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic ox, receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT 1A/7, was also analyzed in computational stud- ies. Moreover, two highly selective (9 and HI) 5-HT₂A receptor antagonists were obtained.

As a continuation of our search for novel histamine H

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9 μM and 20.5 μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.

As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2−25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0–120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.

Serotonin (5-HT) and adrenaline acting at platelet 5-HT2A-serotoninergic and α2-adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT2A, α2A-, and α2B-adrenoceptors as well as an anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and compared them with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239 (2-[2-[4-(o-methoxyphenyl)-piperazin-1-yl]-ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione). Functional bioassays at cells expressing human receptors, revealed studied compounds to be moderate antagonists of 5-HT2A and α2-adrenoceptors, with around 2-7 times stronger antagonistic effect at α2B subtype than α2A subtype. Further, studied compounds inhibited 5-HT2A-mediated contraction in isolated rat aortic rings and 5-HT vasopressor response in rat in vivo. Studied compounds inhibited collagen stimulated whole rat blood aggregation with compound MH-77 (1-[(2,3-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride) being more potent than sarpogrelate or yohimbine. They also inhibited 5-HT/adrenaline-, amplified ADP- or collagen- induced platelet aggregation. Simultaneous, moderate blockade of 5-HT2A serotonin and α2-adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy.

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α1/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.

The aim of this study was to explore the α1-adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α1-adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1 μM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit). In human aortic endothelial cells (HAEC) NO production was examined using a DAF-FM DA fluorescent indicator, whereas in human aortic smooth muscle cells the influence of the title compounds on K+ efflux was evaluated. The vasorelaxant effect of MH-76 and MH-79 was attenuated by endothelium removal, Nω-Nitro- l -arginine methyl ester (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) pretreatment to the level characteristic for α1-adrenoreceptor blocking activity. In addition, the MH-76 and MH-79 induced relaxation was reduced by K+ channels blockers. In endothelium intact rat aorta, MH-76 and MH-79 caused an increase in cGMP level, whereas in HAEC they increased NO generation. In contrast, the reference, quinazoline based α1-antagonist prazosin, did not influence NO production. Our findings suggest that the mechanisms underlying the vasodilatory properties of non-quinazoline based α1-adrenoceptors antagonists MH-76 and MH-79 involve not only α1-adrenoceptor blocking activity but also the activation of the endothelial NO–cGMP signalling pathway and the subsequent opening of K+ channels. Our studies show that such double mechanism of action is superior to pure α1-adrenoceptor blockade, and may be considered as a promising alternative for the prevention and treatment of cardiovascular diseases.

The aim of this study was to explore the α

Serotonin (5-HT) and adrenaline acting at platelet 5-HT

Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H

Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H 3 receptor. Two series of compounds were obtained with a meta - and a para -biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane ( 13 ) with a K i value of 18 nM. Two para -biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine ( 14 ; K i = 25 nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane ( 16 ; K i = 34 nM), classified as antagonists in a cAMP accumulation assay ( IC 50 = 4 and 9 nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED 50 of 2.72 mg/kg and 1.75 mg/kg respectively), and showed high selectivity (hH 4 R vs hH 3 R > 600-fold) and low toxicity (hERG inhibition: IC 50 > 1.70 µM; hepatotoxicity IC 50 > 12.5 µM; non-mutagenic up to 10 µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.

The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and β-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and β-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and β-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and β-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.

A series of 1,4-disubstituted piperazine derivatives with α 1 -adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity in vitro and in vivo. Most of them displayed strong antiarrhythmic activity in the adrenaline induced model of arrhythmia and in the rat coronary artery ligation-reperfusion model. Their antiarrhythmic effect is mainly related to α 1 -adrenolytic properties. Among them one compound showed characteristics similar to quinidine in different arrhythmia models as well as electrocardiogram (ECG) studies which suggests that it possesses not only α 1 -adrenoceptor blocking properties but also affinity for cardiac Na + and K + channels, similar to class IA antiarrhythmic agents. Two other compounds revealed some antioxidant effects. Another compound (MH-79) is particularly promising since it displayed a strong antiarrhythmic effect without the influence on ECG record.

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their relaxant effects in the rat aorta. Evaluation of prepared derivatives demonstrated that compound (8a) is probably a non-selective phosphodiesterase (PDE) inhibitor, as it induced aortic relaxation through endothelium-independent mechanism.

Since serotonin (5-HT) is strongly involved in the etiology and pathophysiology of depression, the development of new antidepressants is still based on the serotonergic system. The complexity of serotonergic system provides an opportunity for the development of compounds with multiple and complementary mechanism of action. This study describes serotonin receptor profile, functional characterization, and pharmacological in vivo evaluation of new aroxyalkyl derivatives of 2-methoxyphenylpiperazine. The obtained results allowed for the identification of compound 3, (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride), a partial 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, with high affinity toward 5-HT7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT1A receptor activation is crucial for the antidepressant-like activity of compound 3. The rest of the compounds (except compounds 1 and 9) showed antidepressant but not anxiolytic-like properties, which did not result from 5-HT1A receptors activation. Furthermore, the compounds are 5-HT1A and weak 5-HT3 receptors antagonists, and some of them 5-HT2A antagonists. Moreover, none of the studied compounds impaired motor coordination at antidepressant-like doses. Since the studied compounds exhibited activity in behavioral assays and interacted with various receptors, the results of our experiments are very promising and require further studies.

The aim of this study was to evaluate the analgesic as well as anti-inflammatory activities of the new pyrrolo[3,4-d]pyridazinone derivatives. Moreover, the present study attempted to assess some of the mechanisms involved in the pharmacological activity of these compounds. In the previous studies it was shown that these compounds were highly active in the phenylbenzoquinone-induced ‘writhing syndrome’ test and had much lower activity in the hot plate, which indicates that mainly peripheral mechanisms of analgesia are involved in their effects. In these extended studies the analgesic activity of two tested compounds (4c, 4f) was confirmed in some animal models of pain. The studied compounds showed a significant and dose-related antinociceptive effect in the models of pain induced by formalin, capsaicin and glutamic acid. Both compounds decreased the edema formation and one of them (4c) attenuated mechanical hyperalgesia in carrageenan-induced paw inflammation in rats. Furthermore, both compounds inhibited cell migration, plasma exudation and nociceptive reaction in zymosan A-induced mouse peritonitis. In the subsequent studies, including experiments on isolated organs (ileum, trachea, aorta), radioligand assays and biochemical tests, it was demonstrated that analgesic and anti-inflammatory effects of the investigated structures are largely due to their competitive antagonism for histamine H 1 receptor. The influence on the level of cAMP in inflammatory cells (shown in RAW 264.7 macrophages) and subsequent inhibition of cytokine (TNFα, IL-1β) release can also be one of the important mechanisms of their action. Moreover some additional mechanisms may also be involved in the eventual analgesic effect of tested pyrrolo[3,4-d]pyridazinone derivatives.

The present study was designed to investigate the central nervous system activity of terpene GABA (and piracetam) derivatives designated as BF-1, BF-2, BF-3, BF-4, BF-5, BF-6. We assessed their anticonvulsant activity in the two main mouse models of seizures (MES-test, PTZ-test), an antidepressant-like effect in the forced swim test (FST), as well as an influence on spontaneous locomotor activity. Our study demonstrated the strong anticonvulsant activity of (1S,3R,7R)-(-)-3,8,8-trimethyl-4-aza-bicyclo[5.1.0]acetate-5-one hydrochloride (compound BF-2) in the PTZ-test. Activity of BF-2 was equipotent to ethosuximide (380 mg/kg, po) in the PTZ-test, when used at a dose of 100 mg/kg, po. No neurotoxic effects were demonstrated by administration of all tested compounds. Moreover, BF-2, BF-3, BF-6 compounds significantly reduced the immobility time in FST at both doses (by 21-50%), while BF-5 induced a significant anti-immobility effect only when used at a dose of 100 mg/kg (by 39%). The compound BF-6 used at the dose of 30 mg/kg was the most active (50% reduction), and the effect was similar to the result obtained with classical antidepressant--imipramine. The motor stimulatory activity was demonstrated by BF-1 compound at the dose of 100 mg/kg with no effect at a lower (30 mg/kg) dose. On the other hand, the BF-3 at 30 mg/kg significantly decreased spontaneous activity during 30 min observation period, while no alteration in this activity during 6-min observation was detected. At present, it is not possible to indicate which mechanisms of novel, active terpene GABA derivatives are involved in the demonstrated antidepressant-like activity. Although further studies are needed to solve this issue, these data suggest a potential value of the examined terpene GABA derivatives.

The 5-HT6 is one of the most recent additions to the 5-HT receptor family. Its pharmacological profile and anatomical distribution is suggestive of a putative role in mood disorders. Most of preclinical evidence suggests an anxiolytic-like action of 5-HT6 receptor antagonists. Evaluation the anxiolytic-like effects of EMD 386088, a partial 5-HT6receptor agonist, and its putative mechanism of action in rats. EMD 386088, administered intraperitoneally at a dose of 2.5 mg/kg evoked specific anxiolytic-like activity in the automated version of the conflict drinking Vogel and the elevated plus-maze tests visible by increasing all parameters indicating a potential anti-anxiety effect. Its activity was blocked by the selective 5-HT6 receptor antagonist SB 271046, but not by the selective GABAA/benzodiazepine receptor antagonist flumazenil. EMD 386088 did not intensify an anxiolytic-like effect produced by diazepam in the elevated plus-maze test. These findings suggest that EMD 386088, a 5-HT6 receptor agonist, produces anxiolytic-like activity after systemic administration which may result from direct stimulation of 5-HT6 receptors.

The main goal of this study was to assess antiarrhythmic and hypotensive activity of new 2-methoxyphenylpiperazine derivatives of xanthone. In order to better understand mechanism of action of studied compounds, their abilities to antagonize the increase in blood pressure elicited by adrenaline, noradrenaline and methoxamine, as well as the antagonistic properties for α1-adrenoceptors on isolated rat aorta were evaluated. Therapeutic antiarrhythmic activity was investigated in an adrenaline-induced model of arrhythmia. Hypotensive activity in normotensive rats was evaluated after oral administration. Influence on blood vasopressor response and α1-adrenoceptors in rat thoracic aorta was evaluated to determine if the observed cardiovascular effects could be related to α1-adrenolytic properties. Tested compounds produced antiarrhythmic and hypotensive activity. The most active compound was MH-99 – (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride. All studied compounds showed α1-adrenolytic properties in the in vivo and in vitro tests. The results indicate that the new valuable compounds with antiarrhythmic and hypotensive activity might be found in the group of xanthone derivatives. Further pharmacological utility of these compounds should be investigated.

The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer–Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ∼ 0.8–353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40–3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.

In the search for new hypotesive agents a series of aroxyalkyl derivatives of 2-methoxyphenylpiperazine was obtained. The aim of the present study was to examine their hypotensive properties and to evaluate their mechanism of action. In the study their hypotensive activity after i.v. and p.o. administration, influence on the pressor responses to adrenaline, noradrenaline and methoxamine, direct spasmolytic and vasorelaxant effects were assessed. In the next step two compounds which were the most active and selective for α(1)-adrenoceptors were evaluated for their α(1)-adrenoreceptor subtypes selectivity in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested aroxyalkyl derivatives of 2-methoxyphenylpiperazine is mainly a result of their α(1)- or α(1)/α(2)-adrenoceptor blocking properties. The two most active compounds showed to be the competitive antagonists of α(1)-adrenoceptors with stronger activity at α(1D)-, α(1A)- and α(1L)- and weaker at α(1B)-subtype.