Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2‑Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice

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 6–9 that as positive allosteric modulators
(PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative
atypical type I PAM 6p exhibits potent activation of
α7 current with an EC50 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 6p as the substitution
of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 μM; 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.