title: Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.
abstract: A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Giguere
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Schmerberg
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Pogorelov
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhu
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D000697:Central Nervous System Stimulants; D003071:Cognition / Q000187:drug effects*; D003913:Dextroamphetamine; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy / Q000523:psychology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D012565:Schizophrenic Psychology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000697:Central Nervous System Stimulants; D051638:Ether-A-Go-Go Potassium Channels; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D003913:Dextroamphetamine