Designing Chromane Derivatives as α2A-Adrenoceptor Selective Agonists via Conformation Constraint

  • J Med Chem. 2024 Jun 18. doi: 10.1021/acs.jmedchem.4c01239.
Xucheng Lv  1 ,  Peilan Zhou  1 ,  Xuehong Qiao  1  2 ,  Yulei Li  1 ,  Xingxing Yang  1  2 ,  Jiaqi Wang  1 ,  Xinhua He  1 ,  Ruibin Su  1
Affiliations
  • 1. Beijing Institute of Pharmacology and Toxicology, Haidian District, Beijing 100850, China.
  • 2. Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 38889119 DOI: 10.1021/acs.jmedchem.4c01239
Abstract

Enhancing the selectivity of alpha2-adrenoceptor (α2A-AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A-AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A-AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10-80 fold. In vivo studies demonstrated that both A9 and B9 dose-dependently increased the loss of righting reflex in mice, with ED50 values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP1283.32 and α2A-AR agonist. In particular, A9 and B9 showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α2A-AR activation.

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