Work

Discovery and characterization of quinoxaline and quinoline carboxamides as allosteric cannabinoid receptor modulators

Year: 2025

Type: article

Abstract: Cannabinoid (CB) receptors type 1 (CB 1 ) and type 2 (CB 2 ) are G i protein-coupled receptors that play important roles in brain function and immune regulation. While orthosteric CB 1 and CB 2 receptor agonists and antagonists have been widely studied, only few allosteric modulators are known. Screening of a proprietary compound library led to the discovery of quinoxaline-6-carboxamides as novel allosteric modulators of CB receptors. N -(4-Ethylphenyl)quinoxaline-6-carboxamide ( 3j , PSB-18579) acted as a negative allosteric CB 1 receptor modulator as determined in β-arrestin-2 recruitment assays (IC 50 6.78 µM), but had no effect on agonist-induced G i protein dissociation, while it enhanced agonist radioligand binding to the receptor. Docking studies predicted its interaction with an allosteric site previously elucidated by X-ray crystallography. In contrast, the related N -(2-(benzyloxy)phenyl)quinoline-6-carboxamide ( 4a , PSB-21644) behaved as a potent partial CB 2 receptor agonist, showing nanomolar potency in β-arrestin-2 recruitment assays (EC 50 0.0371 µM, E max 65 %). Schild plot analysis suggested an allosteric interaction of 4a with the human CB 2 receptor. Similar potency and efficacy were observed in cyclic adenosine monophosphate (cAMP) accumulation assays (EC 50 0.0765 µM, E max 57 %). These findings provide new lead structures for the development of allosteric modulators of CB receptors, which constitute important drug targets

Source: Biochemical Pharmacology

DOI: 10.1016/j.bcp.2025.117485

Authors: Chunyang Bi, Andhika B. Mahardhika, Thanigaimalai Pillaiyar, Christa E. Müller

Institution: University of Bonn

Language: English

Topic: Cannabis and Cannabinoid Research

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,590