title: Chemistry and pharmacology of nicotinic ligands based on 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol (AMOP-H-OH) for possible use in depression.
abstract: AMOP-H-OH (sazetidine-A; 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) and some sulfur-bearing analogues were tested for their activities in vitro against human alpha4beta2-, alpha4beta4-, alpha3beta4*- and alpha1*-nicotinic acetylcholine receptors (nAChRs). AMOP-H-OH was also assessed in an antidepressant efficacy model. AMOP-H-OH and some of its analogues have high potency and selectivity for alpha4beta2-nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (alpha4)(3)(beta2)(2)-nAChRs. More prolonged exposure to AMOP-H-OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for alpha4beta2-nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of alpha4beta2-nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP-H-OH and some of its analogues have a set of binding sites on alpha4beta2-nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP-H-OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP-H-OH also has profound and high potency antidepressant-like effects in the forced swim test. The net action of prolonged exposure to AMOP-H-OH or its analogues, as for nicotine, seems to be a selective decrease in alpha4beta2-nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.
authors: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA. kozikowa@uic.edu
authors: Alan P
authors: AP
authors: Kozikowski
authors: J Brek
authors: JB
authors: Eaton
authors: Krishna Mohan
authors: KM
authors: Bajjuri
authors: Sheela K
authors: SK
authors: Chellappan
authors: Yihua
authors: Y
authors: Chen
authors: Sudhakar
authors: S
authors: Karadi
authors: Rong
authors: R
authors: He
authors: Barbara
authors: B
authors: Caldarone
authors: Michael
authors: M
authors: Manzano
authors: Po-Wai
authors: PW
authors: Yuen
authors: Ronald J
authors: RJ
authors: Lukas
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology; D001384:Azetidines / Q000737:chemistry* / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D006801:Humans; D008024:Ligands; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D001384:Azetidines; D008024:Ligands; D020033:Protein Isoforms; D011725:Pyridines; D011978:Receptors, Nicotinic; C082735:azetidine