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
posted on 2024-02-23, 17:12authored byChenxia Yang, Ying Meng, Xintong Wang, Xin Li, Tong Yu, Weiming Liao, Wenjun Xie, Qianchen Jiang, Han Wang, Cheng Shi, Wenxuan Jiao, Xiling Bian, Fang Hu, Xiaowei Wang, Yani Liu, Liangren Zhang, KeWei Wang, Qi Sun
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.