The Experts below are selected from a list of 5661 Experts worldwide ranked by ideXlab platform
William E. Fantegrossi - One of the best experts on this subject based on the ideXlab platform.
-
discriminative stimulus effects of psychostimulants and hallucinogens in s 3 4 methylenedioxymethamphetamine mdma and r mdma trained mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
-
Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
David E Nichols - One of the best experts on this subject based on the ideXlab platform.
-
Steric Effects of Substituents on Phenethylamine Hallucinogens. 3,4- (Met hy1enedioxy)amphetamine Analogues Alkylated on the Dioxole Ring Notes
2015Co-Authors: David E Nichols, Linda J. KostubaAbstract:aminopropane were synthesized and evaluated for pharmacologic effects in mice. These can be viewed as analogues of the known psychotomimetic agent 3,4-(methy1enedioxy)amphetamine (MDA). Their hydrochloride salts were compared with MDA for their ability to increase spontaneous motor activity and to elicit behavioral effects. The former compound was MDA-like in action, while the latter was not. The results suggest that one face of the molecule must be free of steric bulk to possess activity. A new model was recently proposed which interrelates the structures of Phenethylamine hallucinogens with the tryptamines and LSD.’-3 Based upon the known relative planarity of the LSD molecule, it was assumed that in-teraction with the receptor is of an essentially planar nature. In contrast, the Phenethylamine hallucinogens are very flexible and little is actually known regarding the steric or conformational properties of these types of molecules upon receptor interaction. At the para position, straight-chain alkyls but not a tert-butyl substituent possess a ~ t i v i t y. ~ Decreased hallucinogenic activity in certain 2,3-dimethoxy-substituted compounds has been interpreted to mean that steric crowding adjacent to the side chain cannot be tolerated. These facts could indicate a requirement for a planar interaction between the Phenethylamines and the receptor. However, steric bulk may be tolerated on one face of the molecule. This is supported by the fact that compounds with a p-iso-propoxy5 or p-(isopropylthio)6 substituent retain activity. Rotation about the Ar-0 or Ar-S bond allows these groups to clear one face of the molecule, whereas with a tert-butyl attached directly to the ring no such steric relief is possible. As an attempt to explore these ideas, we have syn-thesized and carried out a preliminary pharmacological evaluation of compounds 1 and 2, which can be viewed t
-
molecular interaction of serotonin 5 ht2a receptor residues phe339 6 51 and phe340 6 52 with superpotent n benzyl Phenethylamine agonists
Molecular Pharmacology, 2006Co-Authors: Michael R Braden, Jason C Parrish, John C Naylor, David E NicholsAbstract:Experiments were conducted to examine the molecular basis for the high affinity and potency of a new class of 5-HT(2A) receptor agonists, N-benzyl Phenethylamines. Competition binding assays at several serotonin receptors confirmed that an N-arylmethyl substitution was necessary for affinity increases up to 300-fold over simple N-alkyl homologs, as well as enhanced selectivity for 5-HT(2A) versus 5-HT(2C) and 5-HT(1A) receptors. PI hydrolysis functional assays confirmed that these N-benzyl Phenethylamines are potent and highly efficacious agonists at the rat 5-HT(2A) receptor. Virtual docking of these compounds into a human 5-HT(2A) receptor homology model indicated that the N-benzyl moiety might be interacting with Phe339((6.51)), whereas the Phenethylamine portion was likely to be interacting with Phe340((6.52)). Experiments in h5-HT(2A) receptors with Phe339((6.51))L and Phe340((6.52))L mutations seem to support this hypothesis. Dramatic detrimental effects on affinity, potency, and intrinsic activity were observed with the Phe339((6.51))L mutation for all N-benzyl analogs, whereas most N-unsubstituted Phenethylamines and traditional agonists were only weakly affected, if at all. Consistent with other published studies, the Phe340((6.52))L mutation detrimentally affected affinity, potency, and intrinsic activity of nearly all compounds tested, although a strong change in intrinsic activity was not seen with most N-aryl analogs. These data further validate the topology of our h5-HT(2A) receptor homology model. It is noteworthy that this study is the first to identify a hitherto unrecognized role for residue 6.51 in agonist activation of a serotonin G protein-coupled receptor (GPCR), whereas most previous reports have suggested a varied and sometimes contradictory role in homologous GPCRs.
-
differential phospholipase c activation by phenylalkylamine serotonin 5 ht2a receptor agonists
Journal of Neurochemistry, 2005Co-Authors: Jason C Parrish, Michael R Braden, Emily Gundy, David E NicholsAbstract:Experiments compared a series of Phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT2A receptors. The (±)phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their Phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)- and (S)-phenylisopropylamines with their Phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies. In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their Phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered.
Kevin S. Murnane - One of the best experts on this subject based on the ideXlab platform.
-
discriminative stimulus effects of psychostimulants and hallucinogens in s 3 4 methylenedioxymethamphetamine mdma and r mdma trained mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
-
Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
Naoki Murai - One of the best experts on this subject based on the ideXlab platform.
-
discriminative stimulus effects of psychostimulants and hallucinogens in s 3 4 methylenedioxymethamphetamine mdma and r mdma trained mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
-
Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
Leonard L. Howell - One of the best experts on this subject based on the ideXlab platform.
-
discriminative stimulus effects of psychostimulants and hallucinogens in s 3 4 methylenedioxymethamphetamine mdma and r mdma trained mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
-
Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kevin S. Murnane, Leonard L. Howell, Naoki Murai, William E. FantegrossiAbstract:3,4-Methylenedioxymethamphetamine (MDMA) is a substituted Phenethylamine more commonly known as the drug of abuse “ecstasy.” The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted Phenethylamines, R(−)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(−)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar Phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar Phenethylamine 5-hydroxytryptamine (5-HT)2A agonist 2,5-dimethoxy-4-(n)-propylthioPhenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(−)-MDMA cue. 2C-T-7 fully substituted in the R(−)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(−)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
