Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Medifron DBT, Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
Eur J Med Chem. 2019 Nov 15;182:111634. doi: 10.1016/j.ejmech.2019.111634. Epub 2019 Aug 21.
In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.
为了发现一种新型的镇痛药，我们研究了具有 TRPV1 拮抗作用和μ-阿片受体亲和力的双重活性配体，以期在避免单靶点相关副作用的同时产生协同镇痛作用。基于组合方法，设计、合成了一系列 4-苄基-4-(二甲基氨基)哌啶基类似物，并对其受体活性进行了评价。其中，化合物 49 在体外对 TRPV1 和μ-阿片受体表现出最有希望的双重作用活性。在体内，49 在福马林测定中第 1 相和第 2 相均表现出强大的、剂量依赖性的镇痛活性。与预期的作用机制一致，我们证实化合物 49 在体内与体外一样，既能拮抗 TRPV1，又能作为μ-阿片受体激动剂发挥作用。这一结果表明，双重作用的 TRPV1 拮抗剂/μ-阿片受体配体是可以制成的，代表了一类新的、有前途的镇痛药。
