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-d]­pyrimidin-7­(6H)-ones (3aa–3eq) were designed,
synthesized, and evaluated as the type I positive allosteric modulators
of human α7 nAChR expressed in Xenopus ooctyes
by a two-electrode voltage clamp. The structure–activity relationship
analysis identified the compound 3ea 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-HT3A, NMDA, and GABAA receptors. Compound 3ea 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 3ea dose-dependently (0.1–1
mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801
in the mouse schizophrenia model.