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
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 Î±4Î²2-, Î±4Î²4-, Î±3Î²4*- and Î±1*-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 Î±4Î²2-nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (Î±4) 3 (Î²2) 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 Î±4Î²2-nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of Î±4Î²2-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 Î±4Î²2-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 Î±4Î²2-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. Â© 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
Digital Object Identifier (DOI)
Kozikowski, Alan P.; Eaton, J. Brek; Bajjuri, Krishna Mohan; Chellappan, Sheela K.; Chen, Yihua; Karadi, Sudhakar; He, Rong; Caldarone, Barbara; Manzano, Michael; Yuen, Po Wai; and Lukas, Ronald J., "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" (2009). Translational Neuroscience. 197.