Pharmacological characterization of a new synthesis compound with antagonistic action on CB1 receptors: Evidence from the animal experimental model

Abstract

The endocannabinoid system is implicated in multiple physiological and pathological processes, making it a promising target for therapeutic intervention. CB1 receptor antagonists have shown potential in treating metabolic, neuropsychiatric, and addiction-related disorders. However, the adverse effects of CB1 antagonists like rimonabant have spurred the development of new compounds with improved safety profiles. This study investigates the pharmacological effects of a novel synthetic compound, 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-2-phenylchinazolin-4(3H)-one (QD13), a quinazolinone derivative designed to antagonize CB1 receptor activity selectively. Molecular docking studies were conducted to assess the binding affinity of QD13 at the CB1 receptor, comparing it to the reference antagonist AM6538. The effects of QD13 were evaluated using the tetrad task in C57Bl/6 mice. The ability of QD13 to antagonize the effects of the CB1 agonist CP55,940 on locomotor activity, body temperature, catalepsy, and nociception were measured. Additionally, isolated ileum preparations were used to determine QD13's impact in counteracting the effects of CB1 agonists on gastrointestinal contractility. Docking analysis confirmed QD13's occupation of the CB1 receptor binding site, overlapping with AM6538, suggesting strong affinity. QD13 dose-dependently reversed CP55,940-induced hypomotility, catalepsy, analgesia, and hypothermia, with significant effects observed at 1 mg/kg and 3 mg/kg. Moreover, QD13 counteracted CP55,940-induced inhibition of ileal contractility, supporting its antagonistic activity in peripheral tissues. QD13 shows promising CB1 receptor antagonistic activity both centrally and peripherally. Its modulation of CB1 effects in the tetrad task and gastrointestinal assays suggests potential therapy for neuropsychiatric disorders, obesity, and addiction. Further studies are needed to clarify QD13's safety and efficacy.