Design and Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice

A series of novel thiazolo­[4,5-<i>d</i>]­pyrimidin-7­(6<i>H</i>)-ones (<b>3aa</b>–<b>3eq</b>) were designed, synthesized, and evaluated as the type I positive allosteric modulators of human α7 nAChR expressed in <i>Xenopus</i> ooctyes by a two-electrode voltage clamp. The structure–activity relationship analysis identified the compound <b>3ea</b> as a potent and efficacious PAM with the maximum activation effect of the α7 current of over 1633% in the presence of acetylcholine (100 μM) and an EC₅₀ = 1.26 μM. It is highly specific to α7 nAChR over other subtypes of nAChR, 5-HT_3A, NMDA, and GABA_A receptors. Compound <b>3ea</b> showed an elimination half-life of 10.8 ± 1.5 h for 3 mg/kg, i.v., and 7.4 ± 1.1 h for 60 mg/kg, i.g. in rat. It also exhibited sufficient blood–brain barrier penetration with no significant effect on hERG channel. Most importantly, compound <b>3ea</b> dose-dependently (0.1–1 mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801 in the mouse schizophrenia model