Allosteric Activation of 7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice

Enhancing alpha 7 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 6-9 that as positive allosteric modulators (PAMs) activate human alpha 7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of alpha 7 current with an EC50 of 1.3 mu M and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 mu M). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of alpha 7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 mu M; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition. [GRAPHICS]