2. Academic Validation
  3. 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

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

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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