title: Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
abstract: 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 and 5-HT2B receptor.
authors: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors: Jianjun
authors: J
authors: Cheng
authors: Patrick M
authors: PM
authors: Giguère
authors: Oluseye K
authors: OK
authors: Onajole
authors: Wei
authors: W
authors: Lv
authors: Arsen
authors: A
authors: Gaisin
authors: Hendra
authors: H
authors: Gunosewoyo
authors: Claire M
authors: CM
authors: Schmerberg
authors: Vladimir M
authors: VM
authors: Pogorelov
authors: Ramona M
authors: RM
authors: Rodriguiz
authors: Giulio
authors: G
authors: Vistoli
authors: William C
authors: WC
authors: Wetsel
authors: Bryan L
authors: BL
authors: Roth
authors: Alan P
authors: AP
authors: Kozikowski
mesh_terms: D000498:Allyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000661:Amphetamine; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000597471:(2-(2-(allyloxy)-5-fluorophenyl)cyclopropyl)methanamine; D000498:Allyl Compounds; D014150:Antipsychotic Agents; D008744:Methylamines; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D003577:Cytochrome P-450 Enzyme System; D000661:Amphetamine
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