Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of ?7 nicotinic acetylcholine receptors.

ABSTRACT: A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of ?7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human ?7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 ?M. Compound 7z was active in reversing the effect of scopolamine in the novel object recognition (NOR) paradigm with a minimum effective ip dose of 1.0 mg/kg (2.7 ?mol/kg). This effect was blocked by the selective ?7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of ?7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer's disease.

SUBMITTER: Hogenkamp DJ 

PROVIDER: S-EPMC3912855 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature