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

  • J Med Chem. 2024 Feb 23. doi: 10.1021/acs.jmedchem.3c02323.
Chenxia Yang  1 ,  Ying Meng  2 ,  Xintong Wang  2 ,  Xin Li  2 ,  Tong Yu  2 ,  Weiming Liao  2 ,  Wenjun Xie  2 ,  Qianchen Jiang  2 ,  Han Wang  2 ,  Cheng Shi  2 ,  Wenxuan Jiao  2 ,  Xiling Bian  2 ,  Fang Hu  1 ,  Xiaowei Wang  2 ,  Yani Liu  1  3 ,  Liangren Zhang  2 ,  KeWei Wang  1  3 ,  Qi Sun  2
Affiliations
  • 1. Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
  • 2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 3. Institute of Innovative Drugs, 38 Dengzhou Road, Qingdao University, Qingdao 266021, China.
PMID: 38393821 DOI: 10.1021/acs.jmedchem.3c02323
Abstract

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.

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