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

Alan P. Kozikowski, J. Brek Eaton, Krishna Mohan Bajjuri, Sheela K. Chellappan, Yihua Chen, Sudhakar Karadi, Rong He, Barbara Caldarone, Michael Manzano, Po Wai Yuen, Ronald J. Lukas

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1279-1291
Number of pages13
JournalChemMedChem
Volume4
Issue number8
DOIs
StatePublished - Aug 3 2009

Keywords

  • AMOP-H-OH
  • Depression
  • Neurological agents
  • Nicotine
  • Receptors
  • Sazetidine-A
  • nAChRs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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