title: Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile.
abstract: Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Hankun
authors.initials: H
authors.lastname: Zhang
authors.forename: Werner
authors.initials: W
authors.lastname: Tückmantel
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.forename: Krishna Mohan
authors.initials: KM
authors.lastname: Bajjuri
authors.forename: Allison
authors.initials: A
authors.lastname: Fedolak
authors.forename: Daguang
authors.initials: D
authors.lastname: Wang
authors.forename: Afshin
authors.initials: A
authors.lastname: Ghavami
authors.forename: Barbara
authors.initials: B
authors.lastname: Caldarone
authors.forename: Neil E
authors.initials: NE
authors.lastname: Paterson
authors.forename: David A
authors.initials: DA
authors.lastname: Lowe
authors.forename: Daniela
authors.initials: D
authors.lastname: Brunner
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002460:Cell Line; D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2