Nguyen Thuy, Decker Ann M, Barrus Daniel G, Song Chi Hyuck, Liu Jianfeng, Gamage Thomas F, Harris Danni L, Li Jun-Xu, Zhang Yanan
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27713, United States.
Department of Pharmacology and Toxicology, University at Buffalo, the State University of New York, Buffalo, New York 14203, United States.
J Med Chem. 2025 Apr 24;68(8):8694-8712. doi: 10.1021/acs.jmedchem.5c00383. Epub 2025 Apr 8.
Cannabinoid receptor type 1 (CB) negative allosteric modulators have emerged as an alternate approach to CB orthosteric antagonists/inverse agonists for cocaine addiction treatment. This study explores aryl-alkyl squaramides as CB allosteric modulators, featuring RTICBM-262 () with good in vitro potencies in CB calcium mobilization, [S]GTPγS binding, and cAMP assays. Molecular modeling studies suggest bound in a similar pocket as Org27569, forming π-stacking with key residues H154 and W241, and the potential C98-C107 disulfide bond had limited impact on its binding or receptor activation. ADME and in vivo pharmacokinetic studies suggest that had reasonable metabolic stability, brain penetration, and selectivity against a panel of ∼ 50 targets but poor solubility and high protein binding. At 5.6 mg/kg (i.p.), significantly attenuated both cocaine-seeking behavior specific to cue-induced reinstatement and cocaine-induced behavioral sensitization without altering locomotor activity. These results support squaramides as promising candidates for further investigation for cocaine addiction treatment.
1型大麻素受体（CB）负变构调节剂已成为治疗可卡因成瘾的一种替代方法，可替代CB正构拮抗剂/反向激动剂。本研究探索芳基烷基方酰胺作为CB变构调节剂，其中RTICBM-262（）在CB钙动员、[S]GTPγS结合和cAMP测定中具有良好的体外效力。分子模拟研究表明，其与Org27569结合在相似的口袋中，与关键残基H154和W241形成π堆积，潜在的C98-C107二硫键对其结合或受体激活影响有限。药物代谢动力学和体内药代动力学研究表明，其具有合理的代谢稳定性、脑渗透性以及对约50种靶点的选择性，但溶解度差且蛋白结合率高。腹腔注射5.6mg/kg时，其显著减弱了线索诱导复吸所特有的可卡因寻求行为以及可卡因诱导的行为敏化，而不改变运动活性。这些结果支持方酰胺作为治疗可卡因成瘾进一步研究的有前景的候选物。
