TY - JOUR
T1 - Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists
T2 - Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models
AU - Cheng, Jianjun
AU - Giguere, Patrick M.
AU - Schmerberg, Claire M.
AU - Pogorelov, Vladimir M.
AU - Rodriguiz, Ramona M.
AU - Huang, Xi Ping
AU - Zhu, Hu
AU - McCorvy, John D.
AU - Wetsel, William C.
AU - Roth, Bryan L.
AU - Kozikowski, Alan P.
N1 - Funding Information:
Financial support from the National Institute of Mental Health (NIMH) (no. R01MH99993) and Psychoactive Drug Screening Program (PDSP, Contract no. HHSN-271-2013-00017-C) is gratefully acknowledged. We thank Dr. Werner Tueckmantel for proofreading the manuscript and providing valuable suggestions.
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2016/1/28
Y1 - 2016/1/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84970916717&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84970916717&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b01153
DO - 10.1021/acs.jmedchem.5b01153
M3 - Article
C2 - 26704965
AN - SCOPUS:84970916717
SN - 0022-2623
VL - 59
SP - 578
EP - 591
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 2
ER -