Pharmacological Properties And Evaluations Of A Novel Positive Allosteric Modulator Of Alpha 7 Nachr For Attenuation Of Schizophrenia-Like Behavior In Mice

The alpha-7 neuronal nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca2+-permeable ion channel critical for cognition, sensory processing, attention, and working memory. Dysfunctional α7 nAChR is implicated in cognition and neuropsychiatric disorders. Therefore, enhancement of α7 nAChR function is considered to be therapeutic strategy aimed at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. We recently synthesized a novel series of 6-(2-Chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-ones as positive allosteric modulators (PAM) of α7 nAChR. In this study we evaluated the effect of a representative compound JWX-A0108 on activation of α7 and auditory gating or cognitive deficits in mice using a combination of assays including two-electrode voltage clamp (TEVC) recordings of Xenopus oocytes expressing human α7 nAChR, brain slice recordings, pre-pulse inhibition (PPI) for startle response and Y-maze spontaneous alternation test. Compound JWX-A0108 exhibits as type I PAM that specifically activates α7 current in the presence of 100 µM ACh in dose-dependent manner with EC50 at 5.7 ± 0.7 µM and 6-fold increase of the current. Application of JWX-A0108 (1-10 mg/kg, i.p.) dose-dependently reversed the auditory gating deficit induced by NMDA antagonist MK-801 in prepulse inhibition assay. In Y-maze, JWX-A0108 (0.03-0.3 mg/kg, i.p.) significantly increased the time spent in novel arm from 45% to 63% in mice treated with MK-801. We also evaluated the effect of JWX-A0108 on locomotor activity, and fount that JWX-A0108 (0.03 mg/kg, i.p.) significantly reduced MK-801-induced hyperactivity. The effects of JWX-A0108 on selectivity, pERK signaling and synaptic transmissions are currently being investigated.