大麻素类药物:设计比古安胺嵌入式,口服可用,外围选择性大麻素-1受体对手,用于代谢综合征障碍
Szabolcs Dvorácskó1,2, Alexa Herrerias3, Anna Oliverio3
1Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, Maryland 20852, United States.
Journal of medicinal chemistry
|August 23, 2023
概括
开发了新的局限性大麻素-1受体 (CB1R) 抗剂. 这些化合物激活AMPK,在治疗肥胖和相关代谢障碍方面表现出有效性,对大脑的影响最小.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 代谢障碍 代谢障碍 代谢障碍
背景情况:
- 肥胖和相关的并发症对健康构成重大挑战.
- 向大麻素-1受体 (CB1R) 已经显示出治疗潜力,但受到中枢神经系统副作用的限制.
- 激活5'-腺单酸激酶 (AMPK) 是一种有前途的代谢调节策略.
研究的目的:
- 设计和合成新的,口服生物可用,不穿透大脑的CB1R抗剂.
- 为了结合一大化物部分来模仿AMPK激活.
- 评估这些化合物用于治疗与肥胖相关的代谢障碍,并减少神经精神效应.
主要方法:
- 合成一系列的3,4-diarylpyrazolines与设计的外围限制.
- 评估CB1R结合亲和力和对抗活性.
- 在饮食诱导的肥胖小鼠中评估AMPK激活和体内疗效.
主要成果:
- 这些化合物表现出高的CB1R结合亲和力和强大的抗体活性.
- 合成的化合物显示AMPK激活.
- 选择的化合物 (36,38-, 39-) 显示<5%的大脑透率,证实了外围限制.
- 化合物38-减少食物摄入量,体重,改善葡萄糖耐受性和体内胰岛素耐药性.
结论:
- 成功设计和合成了具有AMPK激活特性的新型局部受限CB1R抗剂.
- 这些"大麻胺"化合物为代谢综合征提供了一个有前途的治疗策略.
- 开发的化合物显示出治疗可忽略不计的神经精神疾病副作用的代谢障碍的潜力.
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