title: Synthesis and Behavioral Studies of Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part III.
abstract: We report the synthesis and biological characterization of novel derivatives of 3-[(1-methyl-2(S)-pyrrolidinyl)methoxy]-5-cyclopropylpyridine (4a-f and 5) as potent and highly selective α4β2-nicotinic acetylcholine receptor (nAChR) full or partial agonists. A systematic structure-activity study was carried out on the previously described compound 3b, particularly concerning its (2-methoxyethyl)cyclopropyl side-chain, in an effort to improve its metabolic stability while maintaining receptor selectivity. Compound 4d exhibited very similar subnanomolar binding affinity for α4β2- and α4β2*-nAChRs compared to 3b, and it showed excellent potency in activating high-sensitivity (HS) α4β2-nAChRs with an EC50 value of 8.2 nM. Testing of 4d in the SmartCube assay revealed that the compound has a combined antidepressant plus antipsychotic signature. In the forced swim test at a dose of 30 mg/kg given intraperitoneally, 4d was found to be as efficacious as sertraline, thus providing evidence of the potential use of the compound as an antidepressant. Additional promise for use of 4d in humans comes from pharmacokinetic studies in mice indicating brain penetration, and additional assays show compound stability in the presence of human microsomes and hepatocytes. Thus, 4d has a very favorable preclinical drug profile.
authors.affiliation: 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.|Department of Biological, Chemical and Physical Sciences, Roosevelt University , 425 S. Wabash Avenue, Chicago, Illinois 60605, United States.
authors.forename: Oluseye K
authors.initials: OK
authors.lastname: Onajole
authors.affiliation: 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.forename: Gian Paolo
authors.initials: GP
authors.lastname: Vallerini
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute , 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute , 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.affiliation: PsychoGenics, Inc. , 765 Old Saw Mill River Road, Tarrytown, New York 10591, United States.
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
authors.affiliation: Harvard NeuroDiscovery Center and Department of Neurology, Brigham and Women's Hospital , 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Caldarone
authors.affiliation: 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.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic
keywords: N-methylpyrrolidine; Nicotinic acetylcholine receptors; cyclopropane; selective α4β2 partial agonists