Work

Development of Squaramides as Allosteric Modulators of the CB1 Receptor: Synthesis, Computational Studies, Biological Characterization, and Effects against Cocaine-Induced Behavioral Sensitization and Reinstatement in Rats

Year: 2025

Type: article

Abstract: Cannabinoid receptor type 1 (CB 1 ) negative allosteric modulators have emerged as an alternate approach to CB 1 orthosteric antagonists/inverse agonists for cocaine addiction treatment. This study explores aryl-alkyl squaramides as CB 1 allosteric modulators, featuring RTICBM-262 ( 3 ) with good in vitro potencies in CB 1 calcium mobilization, [ 35 S]GTPγS binding, and cAMP assays. Molecular modeling studies suggest 3 bound in a similar pocket as Org27569, forming π-stacking with key residues H154 2.41 and W241 4.50, and the potential C98–C107 disulfide bond had limited impact on its binding or receptor activation. ADME and in vivo pharmacokinetic studies suggest that 3 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.), 3 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c00383