Design, Synthesis, and Activity of a Series of Arylpyrid-3-ylmethanones as Type I Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors
journal contributionposted on 14.11.2013 by Derk J. Hogenkamp, Thomas A. Ford-Hutchinson, Wen-Yen Li, Edward R. Whittemore, Ryan F. Yoshimura, Minhtam B. Tran, Timothy B. C. Johnstone, Gavin D. Bascom, Hannah Rollins, Lena Lu, Kelvin W. Gee
Any type of content formally published in an academic journal, usually following a peer-review process.
A series of novel arylpyrid-3-ylmethanones (7a–aa) were designed as modulators of α7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human α7 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 μM. 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 μmol/kg). This effect was blocked by the selective α7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of α7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer’s disease.