Plescia Fabiana, Lavanco Gianluca, Zizzo Maria Grazia, D'Amico Cesare, Bellocchio Luigi, Malta Ginevra, Vaccaro Francesca, Cannizzaro Emanuele, Dimino Leila, Plescia Fulvio
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) - Section of Medicinal Chemistry and Technologies, University of Palermo, Palermo, Italy.
Department of Health Promotion Sciences, Maternal and Child Care, Internal Medicine and Medical Specialties' Giuseppe D'Alessandro, University of Palermo, Via del Vespro 133, 90127, Palermo, Italy.
Eur J Pharmacol. 2025 Sep 15;1003:177973. doi: 10.1016/j.ejphar.2025.177973. Epub 2025 Jul 18.
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.
内源性大麻素系统参与多种生理和病理过程，使其成为治疗干预的一个有前景的靶点。CB1受体拮抗剂已显示出治疗代谢、神经精神和成瘾相关疾病的潜力。然而，像利莫那班这样的CB1拮抗剂的不良反应促使人们开发安全性更高的新化合物。本研究调查了一种新型合成化合物3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-1H-吡唑-3-基)-2-苯基喹唑啉-4(3H)-酮（QD13）的药理作用，QD13是一种设计用于选择性拮抗CB1受体活性的喹唑啉酮衍生物。进行了分子对接研究以评估QD13在CB1受体上的结合亲和力，并将其与参考拮抗剂AM6538进行比较。使用C57Bl/6小鼠的四联试验评估QD13的作用。测量了QD13拮抗CB1激动剂CP55,940对运动活动、体温、僵住症和痛觉感受的影响的能力。此外，使用离体回肠制剂来确定QD13在抵消CB1激动剂对胃肠收缩性的影响方面的作用。对接分析证实QD13占据了CB1受体结合位点，与AM6538重叠，表明具有强亲和力。QD13剂量依赖性地逆转了CP55,940诱导的运动减少、僵住症、镇痛和体温过低，在1mg/kg和3mg/kg时观察到显著效果。此外，QD13抵消了CP55,940诱导的回肠收缩抑制，支持其在外周组织中的拮抗活性。QD13在中枢和外周均显示出有前景的CB1受体拮抗活性。其在四联试验和胃肠试验中对CB1效应的调节表明对神经精神疾病、肥胖和成瘾具有潜在治疗作用。需要进一步研究以阐明QD13的安全性和有效性。
