The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Matthias E. Liechti - One of the best experts on this subject based on the ideXlab platform.
-
Monoamine Receptor interaction profiles of 4-thio-substituted phenethylamines (2C-T drugs).
Neuropharmacology, 2018Co-Authors: Dino Luethi, Marius C. Hoener, Daniel Trachsel, Matthias E. LiechtiAbstract:Abstract Background 4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine Receptor and transporter interaction profiles of a series of 2C-T drugs. Methods We determined the binding affinities of 2C-T drugs at monoamine Receptors and transporters in human cells that were transfected with the respective Receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT2A) and 5-HT2B Receptors, activation of human trace amine-associated Receptor 1 (TAAR1), and inhibition of monoamine uptake transporters. Results 2C-T drugs had high affinity for 5-HT2A and 5-HT2C Receptors (1–54 nM and 40–350 nM, respectively). With activation potencies of 1–53 nM and 44–370 nM, the drugs were potent 5-HT2A Receptor and 5-HT2B Receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B Receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic Receptors. The compounds had high affinity for the rat TAAR1 (5–68 nM) and interacted with the mouse but not human TAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM). Conclusion The Receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 Receptor interactions. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’
-
Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens
European Neuropsychopharmacology, 2016Co-Authors: Anna Rickli, Olivier D. Moning, Marius C. Hoener, Matthias E. LiechtiAbstract:The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine Receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine Receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B Receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A Receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A Receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic Receptors. In conclusion, the Receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.
-
Pharmacological profile of novel psychoactive benzofurans.
British journal of pharmacology, 2015Co-Authors: Anna Rickli, Marius C. Hoener, Simone Kopf, Matthias E. LiechtiAbstract:Background and Purpose Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro. Experimental Approach We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine and 5-HT uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, dopamine and 5-HT from monoamine-preloaded cells, monoamine Receptor-binding affinity and 5-HT2A and 5-HT2B Receptor activation. Key Results All of the benzofurans inhibited NA and 5-HT uptake more than dopamine uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated Receptor 1 (TA1 Receptor), similar to classic amphetamines. Most benzofurans were partial 5-HT2A Receptor agonists similar to MDMA, but also 5-HT2B Receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 Receptors and also bound to TA1 Receptors. Conclusions and Implications Despite very similar structures, differences were found in the pharmacological profiles of different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with 5-HT Receptors. This pharmacological profile probably results in MDMA-like entactogenic psychoactive properties. However, benzofurans induce 5-HT2B Receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction.
-
monoamine transporter and Receptor interaction profiles of novel psychoactive substances para halogenated amphetamines and pyrovalerone cathinones
European Neuropsychopharmacology, 2015Co-Authors: Anna Rickli, Marius C. Hoener, Matthias E. LiechtiAbstract:The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and Receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine Receptors, and 5-HT2B Receptor activation. Para-(4)-substituted amphetamines, including 4-methylmethcathinone (mephedrone), 4-ethylmethcathinone, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcatinone (flephedrone), and 4-bromomethcathinone, were relatively more serotonergic (lower DAT:SERT ratio) compared with their analogs amphetamine, methamphetamine, and methcathinone. The 4-methyl, 4-ethyl, and 4-bromo groups resulted in enhanced serotonergic properties compared with the 4-fluoro group. The para-substituted amphetamines released NE and DA. 4-Fluoramphetamine, 4-flouromethamphetamine, 4-methylmethcathinone, and 4-ethylmethcathinone also released 5-HT similarly to 3,4-methylenedioxymethamphetamine. The pyrovalerone cathinones 3,4-methylenedioxypyrovalerone, pyrovalerone, α-pyrrolidinovalerophenone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, and 3,4-methylenedioxy-α-pyrrolidinobutiophenone potently inhibited the NET and DAT but not the SERT. Naphyrone was the only pyrovalerone that also inhibited the SERT. The pyrovalerone cathinones did not release monoamines. Most of the para-substituted amphetamines exhibited affinity for the 5-HT2A Receptor but no relevant activation of the 5-HT2B Receptor. All the cathinones exhibited reduced trace amine-associated Receptor 1 binding compared with the non-β-keto-amphetamines. In conclusion, para-substituted amphetamines exhibited enhanced direct and indirect serotonergic agonist properties and are likely associated with more MDMA-like effects. The pharmacological profile of the pyrovalerone cathinones predicts pronounced stimulant effects and high abuse liability.
-
Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs).
Neuropharmacology, 2015Co-Authors: Anna Rickli, Marius C. Hoener, Dino Luethi, Julian Reinisch, Danièle Buchy, Matthias E. LiechtiAbstract:Abstract Background N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the Receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro. Methods We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine Receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B Receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human Receptors or transporters were used (with the exception of trace amine-associated Receptor-1 [TAAR1], in which rat/mouse Receptors were used). Results All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C Receptors and rat TAAR1 (most Ki and EC50: 1 μM), unlike LSD. Conclusion The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of α1 Receptor interactions.
P P Avdonin - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of protein tyrosine phosphatases unmasks vasoconstriction and potentiates calcium signaling in rat aorta smooth muscle cells in response to an agonist of 5 ht2b Receptors bw723c86
Biochemical and Biophysical Research Communications, 2017Co-Authors: Galina Yu. Mironova, P P Avdonin, N V Goncharov, Richard O JenkinsAbstract:In blood vessels, serotonin 5-HT2B Receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-l-arginine (l-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes [Nelson et al., 2012]. The unmasking effect on vasoconstriction can be caused by a shift in the balance of tyrosine phosphorylation in smooth muscle cells (SMC) due to oxidative stress induced inhibition of protein tyrosine phosphatases (PTP). We have demonstrated that BW723C86 which does not cause contraction of rat aorta and mesenteric artery rings, evoked a vasoconstrictor effect in the presence of PTP inhibitors sodium orthovanadate (Na3VO4) or BVT948. BW723C86 induced a weak rise of [Ca2+]i in the SMC isolated from rat aorta; however, after pre-incubation with Na3VO4 the response to BW723C86 increased more than 5-fold. This effect was diminished by protein tyrosine kinase (PTK) inhibitor genistein, inhibitor of Src-family kinases PP2, inhibitor of NADPH-oxidase VAS2870 and completely suppressed by N-acetylcysteine and 5-HT2B Receptor antagonist RS127445. Using fluorescent probe DCFH-DA we have shown that Na3VO4 induces oxidative stress in SMC. In the presence of Na3VO4 BW723C86 considerably increased formation of reactive oxygen species while alone had no appreciable effect on DCFH oxidation. We suggest that oxidative stress causes inhibition of PTP and unmasking of 5-HT2B Receptors functional activity.
Cynthia M Nijenhuis - One of the best experts on this subject based on the ideXlab platform.
-
disturbed development of the enteric nervous system after in utero exposure of selective serotonin re uptake inhibitors and tricyclic antidepressants part 2 testing the hypotheses
British Journal of Clinical Pharmacology, 2012Co-Authors: Cynthia M Nijenhuis, Peter G J Ter Horst, Nienke Van Rein, Bob Wilffert, Lolkje T W De Jongâ Van Den BergAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. In a review of the pharmacologic literature we showed that antidepressant exposure might disturb the development of the enteric nervous system. WHAT THIS STUDY ADDS • In utero exposure to selective serotonin re-uptake inhibitors (SSRIs) in the second and third trimester or to tricyclic antidepressants (TCAs) in the first trimester leads to a significant increase in laxative use compared with non-exposed children. SSRI exposure was not associated with significant increased antidiarrhoeal medication use, but TCA exposure was. AIMS Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. METHODS The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children after in utero exposure to antidepressants (TCA, SSRI, fluoxetine or paroxetine exposed) was compared with no antidepressant exposure. Laxatives and antidiarrhoeal medication use were applied as a proxy for constipation and diarrhoea respectively, which may be associated with disturbed enteric nervous system (ENS) development. RESULTS Children exposed in utero to SSRIs (mainly fluoxetine and paroxetine) in the second and third trimester or to TCAs in the first trimester, more often received laxatives. Combined exposure to TCAs and SSRIs in pregnancy was associated with a 10-fold increase in laxative use. In utero exposure to SSRIs is not associated with antidiarrhoeal medication use compared with non-exposed children. In contrast, antidiarrhoeal medication use was significantly higher in children exposed to TCAs anytime in pregnancy. CONCLUSIONS The increased laxative use after second and third trimester exposure to SSRIs might be explained through the inhibitory effect of the serotonin re-uptake transporter (SERT) and because of selectivity for the 5-HT2B Receptor which affects the ENS. TCA exposure during the first trimester leads to increased laxative use probably through inhibition of the norepinephrine transporter (NET). Exposure of TCAs anytime in pregnancy leads to increase diarrhoeal use possibly through down-regulation of α2-adrenoceptors or up-regulation of the pore forming α1c subunit.
-
disturbed development of the enteric nervous system after in utero exposure of selective serotonin re uptake inhibitors and tricyclic antidepressants part 2 testing the hypotheses
British Journal of Clinical Pharmacology, 2012Co-Authors: Cynthia M Nijenhuis, Bob Wilffert, Peter G J Ter Horst, Nienke Van Rein, Lolkje T W De Jongâ Van Den BergAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. In a review of the pharmacologic literature we showed that antidepressant exposure might disturb the development of the enteric nervous system. WHAT THIS STUDY ADDS • In utero exposure to selective serotonin re-uptake inhibitors (SSRIs) in the second and third trimester or to tricyclic antidepressants (TCAs) in the first trimester leads to a significant increase in laxative use compared with non-exposed children. SSRI exposure was not associated with significant increased antidiarrhoeal medication use, but TCA exposure was. AIMS Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. METHODS The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children after in utero exposure to antidepressants (TCA, SSRI, fluoxetine or paroxetine exposed) was compared with no antidepressant exposure. Laxatives and antidiarrhoeal medication use were applied as a proxy for constipation and diarrhoea respectively, which may be associated with disturbed enteric nervous system (ENS) development. RESULTS Children exposed in utero to SSRIs (mainly fluoxetine and paroxetine) in the second and third trimester or to TCAs in the first trimester, more often received laxatives. Combined exposure to TCAs and SSRIs in pregnancy was associated with a 10-fold increase in laxative use. In utero exposure to SSRIs is not associated with antidiarrhoeal medication use compared with non-exposed children. In contrast, antidiarrhoeal medication use was significantly higher in children exposed to TCAs anytime in pregnancy. CONCLUSIONS The increased laxative use after second and third trimester exposure to SSRIs might be explained through the inhibitory effect of the serotonin re-uptake transporter (SERT) and because of selectivity for the 5-HT2B Receptor which affects the ENS. TCA exposure during the first trimester leads to increased laxative use probably through inhibition of the norepinephrine transporter (NET). Exposure of TCAs anytime in pregnancy leads to increase diarrhoeal use possibly through down-regulation of α2-adrenoceptors or up-regulation of the pore forming α1c subunit.
Marius C. Hoener - One of the best experts on this subject based on the ideXlab platform.
-
Monoamine Receptor interaction profiles of 4-thio-substituted phenethylamines (2C-T drugs).
Neuropharmacology, 2018Co-Authors: Dino Luethi, Marius C. Hoener, Daniel Trachsel, Matthias E. LiechtiAbstract:Abstract Background 4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine Receptor and transporter interaction profiles of a series of 2C-T drugs. Methods We determined the binding affinities of 2C-T drugs at monoamine Receptors and transporters in human cells that were transfected with the respective Receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT2A) and 5-HT2B Receptors, activation of human trace amine-associated Receptor 1 (TAAR1), and inhibition of monoamine uptake transporters. Results 2C-T drugs had high affinity for 5-HT2A and 5-HT2C Receptors (1–54 nM and 40–350 nM, respectively). With activation potencies of 1–53 nM and 44–370 nM, the drugs were potent 5-HT2A Receptor and 5-HT2B Receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B Receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic Receptors. The compounds had high affinity for the rat TAAR1 (5–68 nM) and interacted with the mouse but not human TAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM). Conclusion The Receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 Receptor interactions. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’
-
Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens
European Neuropsychopharmacology, 2016Co-Authors: Anna Rickli, Olivier D. Moning, Marius C. Hoener, Matthias E. LiechtiAbstract:The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine Receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine Receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B Receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A Receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A Receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic Receptors. In conclusion, the Receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.
-
Pharmacological profile of novel psychoactive benzofurans.
British journal of pharmacology, 2015Co-Authors: Anna Rickli, Marius C. Hoener, Simone Kopf, Matthias E. LiechtiAbstract:Background and Purpose Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro. Experimental Approach We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine and 5-HT uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, dopamine and 5-HT from monoamine-preloaded cells, monoamine Receptor-binding affinity and 5-HT2A and 5-HT2B Receptor activation. Key Results All of the benzofurans inhibited NA and 5-HT uptake more than dopamine uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated Receptor 1 (TA1 Receptor), similar to classic amphetamines. Most benzofurans were partial 5-HT2A Receptor agonists similar to MDMA, but also 5-HT2B Receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 Receptors and also bound to TA1 Receptors. Conclusions and Implications Despite very similar structures, differences were found in the pharmacological profiles of different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with 5-HT Receptors. This pharmacological profile probably results in MDMA-like entactogenic psychoactive properties. However, benzofurans induce 5-HT2B Receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction.
-
monoamine transporter and Receptor interaction profiles of novel psychoactive substances para halogenated amphetamines and pyrovalerone cathinones
European Neuropsychopharmacology, 2015Co-Authors: Anna Rickli, Marius C. Hoener, Matthias E. LiechtiAbstract:The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and Receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine Receptors, and 5-HT2B Receptor activation. Para-(4)-substituted amphetamines, including 4-methylmethcathinone (mephedrone), 4-ethylmethcathinone, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcatinone (flephedrone), and 4-bromomethcathinone, were relatively more serotonergic (lower DAT:SERT ratio) compared with their analogs amphetamine, methamphetamine, and methcathinone. The 4-methyl, 4-ethyl, and 4-bromo groups resulted in enhanced serotonergic properties compared with the 4-fluoro group. The para-substituted amphetamines released NE and DA. 4-Fluoramphetamine, 4-flouromethamphetamine, 4-methylmethcathinone, and 4-ethylmethcathinone also released 5-HT similarly to 3,4-methylenedioxymethamphetamine. The pyrovalerone cathinones 3,4-methylenedioxypyrovalerone, pyrovalerone, α-pyrrolidinovalerophenone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, and 3,4-methylenedioxy-α-pyrrolidinobutiophenone potently inhibited the NET and DAT but not the SERT. Naphyrone was the only pyrovalerone that also inhibited the SERT. The pyrovalerone cathinones did not release monoamines. Most of the para-substituted amphetamines exhibited affinity for the 5-HT2A Receptor but no relevant activation of the 5-HT2B Receptor. All the cathinones exhibited reduced trace amine-associated Receptor 1 binding compared with the non-β-keto-amphetamines. In conclusion, para-substituted amphetamines exhibited enhanced direct and indirect serotonergic agonist properties and are likely associated with more MDMA-like effects. The pharmacological profile of the pyrovalerone cathinones predicts pronounced stimulant effects and high abuse liability.
-
Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs).
Neuropharmacology, 2015Co-Authors: Anna Rickli, Marius C. Hoener, Dino Luethi, Julian Reinisch, Danièle Buchy, Matthias E. LiechtiAbstract:Abstract Background N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the Receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro. Methods We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine Receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B Receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human Receptors or transporters were used (with the exception of trace amine-associated Receptor-1 [TAAR1], in which rat/mouse Receptors were used). Results All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C Receptors and rat TAAR1 (most Ki and EC50: 1 μM), unlike LSD. Conclusion The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of α1 Receptor interactions.
Bryan L Roth - One of the best experts on this subject based on the ideXlab platform.
-
discovery of n substituted 2 phenylcyclopropyl methylamines as functionally selective serotonin 2c Receptor agonists for potential use as antipsychotic medications
Journal of Medicinal Chemistry, 2017Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P KozikowskiAbstract:A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C Receptor, is fully selective over the 5-HT2B Receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C Receptor with respect to antipsychotic activity.
-
Discovery of N‑Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications
2017Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P KozikowskiAbstract:A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C Receptor, is fully selective over the 5-HT2B Receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C Receptor with respect to antipsychotic activity
-
parallel functional activity profiling reveals valvulopathogens are potent 5 hydroxytryptamine2b Receptor agonists implications for drug safety assessment
Molecular Pharmacology, 2009Co-Authors: Xi Ping Huang, Vincent Setola, Prem N Yadav, John A Allen, Sarah C Rogan, Bonnie J Hanson, Chetana M Revankar, Matt Robers, Chris Doucette, Bryan L RothAbstract:Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) Receptor agonists. We have shown that activation of 5-HT2B Receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT2B Receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT2B Receptor agonists (hits); 14 of these had previously been identified as 5-HT2B Receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then “functionally profiled” (i.e., assayed in parallel for 5-HT2B Receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT2B Receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.
-
parallel functional activity profiling reveals valvulopathogens are potent 5 hydroxytryptamine2b Receptor agonists implications for drug safety assessment
Molecular Pharmacology, 2009Co-Authors: Xi Ping Huang, Vincent Setola, Prem N Yadav, John A Allen, Sarah C Rogan, Bonnie J Hanson, Chetana M Revankar, Matt Robers, Chris Doucette, Bryan L RothAbstract:Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) Receptor agonists. We have shown that activation of 5-HT2B Receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT2B Receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT2B Receptor agonists (hits); 14 of these had previously been identified as 5-HT2B Receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then “functionally profiled” (i.e., assayed in parallel for 5-HT2B Receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT2B Receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.
