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

Department

neurobiology

Document Type

Article

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 α4β2-, α4β4-, α3β4*- and α1*-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 α4β2-nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4) 3 (β2) 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 α4β2-nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2-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 α4β2-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 α4β2-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. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Publication Date

8-3-2009

Publication Title

ChemMedChem

ISSN

18607179

Volume

4

Issue

8

First Page

1279

Last Page

1291

Digital Object Identifier (DOI)

10.1002/cmdc.200900079

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