Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives - that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM exhibits potent activation of α7 current with an EC of 1.3 μM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound as the substitution of 4-methyl group results in its conversion to compound (EC = 2.1 μM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both and are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.
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