Synthesis And Behavioral Studies Of Chiral Cyclopropanes As Selective Î±4Î²2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting An Antidepressant Profile. Part Iii
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 Î±4Î²2-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 Î±4Î²2- and Î±4Î²2âˆ—-nAChRs compared to 3b, and it showed excellent potency in activating high-sensitivity (HS) Î±4Î²2-nAChRs with an EC 50 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.
ACS Chemical Neuroscience
Digital Object Identifier (DOI)
Onajole, Oluseye K.; Vallerini, Gian Paolo; Eaton, J. Brek; Lukas, Ronald J.; Brunner, Dani; Caldarone, Barbara J.; and Kozikowski, Alan P., "Synthesis And Behavioral Studies Of Chiral Cyclopropanes As Selective Î±4Î²2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting An Antidepressant Profile. Part Iii" (2016). Translational Neuroscience. 277.