Chemistry and pharmacological characterization of novel nitrogen analogues of AMOP-H-OH (Sazetidine-A, 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as alpha4beta2-nicotinic acetylcholine receptor-selective partial agonists.

Article Details

Citation Copy to clipboard

Liu J, Eaton JB, Caldarone B, Lukas RJ, Kozikowski AP

J Med Chem. 2010 Oct 14;53(19):6973-85. doi: 10.1021/jm100765u.

PubMed ID

20822184 [ View in PubMed

]

Abstract

In order to advance therapeutic applications of nicotinic ligands, continuing research efforts are being directed toward the identification and characterization of novel nicotinic acetylcholine receptor (nAChR) ligands that are both potent and subtype selective. Herein we report the synthesis and pharmacological evaluation of members of a new series of 3-alkoxy-5-aminopyridine derivatives that display good selectivity for the alpha4beta2-nAChR subtype based on ligand binding and functional evaluations. The most potent ligand in this series, compound 64, showed high radioligand binding affinity and selectivity for rat alpha4beta2-nAChR with a K(i) value of 1.2 nM and 4700-fold selectivity for alpha4beta2- over alpha3beta4-nAChR, and approximately 100-fold selectivity for functional, high-sensitivity, human alpha4beta2-nAChR over alpha3beta4*-nAChR. In the mouse forced swim test, compound 64 exhibited antidepressant-like effects. Structure-activity relationship (SAR) analyses suggest that the introduction of additional substituents to the amino group present on the pyridine ring of the N-demethylated analogue of compound 17 can provide potent alpha4beta2-nAChR-selective ligands for possible use in treatment of neurological and psychiatric disorders including depression.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nicotine	Neuronal acetylcholine receptor subunit beta-2	EC 50 (nM)	300	N/A	N/A	Details
Nicotine	Neuronal acetylcholine receptor subunit beta-2	IC 50 (nM)	430	N/A	N/A	Details