The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform
Paul J Fletcher - One of the best experts on this subject based on the ideXlab platform.
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effects of 5 ht1a 5 ht2a and 5 ht2c Receptor Agonists and antAgonists on responding for a conditioned reinforcer and its enhancement by methylphenidate
Psychopharmacology, 2017Co-Authors: Fiona D Zeeb, Guy A Higgins, Paul J Fletcher, Caleb J Browne, Ashlie D SokoAbstract:Objectives These experiments examined the effects of selective 5-HT1A, 5-HT2A and 5-HT2C Receptor ligands on responding for a conditioned reinforcer (CRf). Effects of these ligands were measured under basal conditions and following elevated dopamine (DA) activity produced by the DA reuptake inhibitor methylphenidate.
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lorcaserin and cp 809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats implications for understanding the anti obesity property of 5 ht2c Receptor Agonists
Psychopharmacology, 2016Co-Authors: Guy A Higgins, Paul J Fletcher, Leo B. Silenieks, Everett B Altherr, Cam Macmillan, Wayne E PrattAbstract:The 5-HT2C Receptor agonist lorcaserin (Belviq®) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders. Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test. Lorcaserin (0.3–0.6 mg/kg SC) and CP-809101 (0.6–1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1–3 mg/kg SC) and CP-809101 (3–6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses. These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C Receptor Agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder.
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the serotonin 2c Receptor agonist lorcaserin attenuates intracranial self stimulation and blocks the reward enhancing effects of nicotine
ACS Chemical Neuroscience, 2015Co-Authors: Fiona D Zeeb, Guy A Higgins, Paul J FletcherAbstract:Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C Receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C Receptor Agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphe nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3–1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C Receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to ni...
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the 5 ht2c Receptor agonist lorcaserin reduces nicotine self administration discrimination and reinstatement relationship to feeding behavior and impulse control
Neuropsychopharmacology, 2012Co-Authors: Guy A Higgins, Paul J Fletcher, Leo B. Silenieks, Anne Rossmann, Zoe Rizos, Kevin Noble, Ashlie D SokoAbstract:Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT2C Receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3–3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6–1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3–1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT2C Receptor Agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT2C Agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.
Jianjun Cheng - One of the best experts on this subject based on the ideXlab platform.
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Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists
2016Co-Authors: Jianjun Cheng, Patrick M Giguere, John D Mccorvy, Bryan L Roth, Hu Zhu, Terry P. Kenakin, Alan P KozikowskiAbstract:On the basis of the structural similarity of our previous 5-HT2C Agonists with the melatonin Receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C Receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C Agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less Receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2C Agonists possessing weak β-arrestin recruitment can produce distinct Receptor desensitization properties
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we need 2c but not 2b developing serotonin 2c 5 ht2c Receptor Agonists for the treatment of cns disorders
ChemMedChem, 2015Co-Authors: Jianjun Cheng, Alan P KozikowskiAbstract:The serotonin 2C (5-HT2C) Receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C Agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the Receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C Agonists make them preferred candidates for further studies.
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optimization of 2 phenylcyclopropylmethylamines as selective serotonin 2c Receptor Agonists and their evaluation as potential antipsychotic agents
Journal of Medicinal Chemistry, 2015Co-Authors: Jianjun Cheng, Patrick M Giguere, Oluseye K Onajole, Arsen Gaisin, Hendra Gunosewoyo, Wei Lv, Claire M SchmerbergAbstract:The discovery of a new series of compounds that are potent, selective 5-HT2C Receptor Agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C Receptor and excellent selectivity against the 5-HT2A and 5-HT2B Receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C Agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C Receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic Receptor ...
Guy A Higgins - One of the best experts on this subject based on the ideXlab platform.
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effects of 5 ht1a 5 ht2a and 5 ht2c Receptor Agonists and antAgonists on responding for a conditioned reinforcer and its enhancement by methylphenidate
Psychopharmacology, 2017Co-Authors: Fiona D Zeeb, Guy A Higgins, Paul J Fletcher, Caleb J Browne, Ashlie D SokoAbstract:Objectives These experiments examined the effects of selective 5-HT1A, 5-HT2A and 5-HT2C Receptor ligands on responding for a conditioned reinforcer (CRf). Effects of these ligands were measured under basal conditions and following elevated dopamine (DA) activity produced by the DA reuptake inhibitor methylphenidate.
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lorcaserin and cp 809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats implications for understanding the anti obesity property of 5 ht2c Receptor Agonists
Psychopharmacology, 2016Co-Authors: Guy A Higgins, Paul J Fletcher, Leo B. Silenieks, Everett B Altherr, Cam Macmillan, Wayne E PrattAbstract:The 5-HT2C Receptor agonist lorcaserin (Belviq®) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders. Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test. Lorcaserin (0.3–0.6 mg/kg SC) and CP-809101 (0.6–1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1–3 mg/kg SC) and CP-809101 (3–6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses. These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C Receptor Agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder.
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the serotonin 2c Receptor agonist lorcaserin attenuates intracranial self stimulation and blocks the reward enhancing effects of nicotine
ACS Chemical Neuroscience, 2015Co-Authors: Fiona D Zeeb, Guy A Higgins, Paul J FletcherAbstract:Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C Receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C Receptor Agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphe nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3–1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C Receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to ni...
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the 5 ht2c Receptor agonist lorcaserin reduces nicotine self administration discrimination and reinstatement relationship to feeding behavior and impulse control
Neuropsychopharmacology, 2012Co-Authors: Guy A Higgins, Paul J Fletcher, Leo B. Silenieks, Anne Rossmann, Zoe Rizos, Kevin Noble, Ashlie D SokoAbstract:Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT2C Receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3–3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6–1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3–1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT2C Receptor Agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT2C Agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.
Alan P Kozikowski - One of the best experts on this subject based on the ideXlab platform.
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Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists
2016Co-Authors: Jianjun Cheng, Patrick M Giguere, John D Mccorvy, Bryan L Roth, Hu Zhu, Terry P. Kenakin, Alan P KozikowskiAbstract:On the basis of the structural similarity of our previous 5-HT2C Agonists with the melatonin Receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C Receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C Agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less Receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2C Agonists possessing weak β-arrestin recruitment can produce distinct Receptor desensitization properties
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we need 2c but not 2b developing serotonin 2c 5 ht2c Receptor Agonists for the treatment of cns disorders
ChemMedChem, 2015Co-Authors: Jianjun Cheng, Alan P KozikowskiAbstract:The serotonin 2C (5-HT2C) Receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C Agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the Receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C Agonists make them preferred candidates for further studies.
Jeffrey M Witkin - One of the best experts on this subject based on the ideXlab platform.
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behavioral effects of a novel benzofuranyl piperazine serotonin 2c Receptor agonist suggest a potential therapeutic application in the treatment of obsessive compulsive disorder
Frontiers in Psychiatry, 2017Co-Authors: Michelle M Rodriguez, Carl D Overshiner, David J Leander, Denise Morrow, Richard Gerard Conway, David L Nelson, Karin Briner, Jeffrey M WitkinAbstract:Selective inhibitors of the neuronal uptake of serotonin (SSRIs) are the only effective pharmacological treatments for OCD. Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) Receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C Receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C Receptors and less potency and partial agonism at 5-HT2A and 5-HT2B Receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C Receptor antagonist SB242084. The 5-HT2C Receptor Agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotorod rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.
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Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder
Frontiers Media S.A., 2017Co-Authors: Michelle M Rodriguez, Carl D Overshiner, David J Leander, Denise Morrow, Richard Gerard Conway, David L Nelson, Karin Briner, Jeffrey M WitkinAbstract:Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) Receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C Receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C Receptors and less potency and partial agonism at 5-HT2A and 5-HT2B Receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C Receptor antagonist SB242084. The 5-HT2C Receptor Agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD
