Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4, Sherbrooke, Québec, Canada.
Angew Chem Int Ed Engl. 2024 Nov 18;63(47):e202405941. doi: 10.1002/anie.202405941. Epub 2024 Oct 14.
The opioid crisis has highlighted the urgent need to develop non-opioid alternatives for managing pain, with an effective, safe, and non-addictive pharmacotherapeutic profile. Using an extensive structure-activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid-independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile residue of NT(7-12) was substituted by cyclopentylalanine, Pro and Pro were replaced by allyl-glycine followed by side-chain to side-chain cyclization is the most selective analog targeting NTS2 identified to date (K 2.9 nM), showing 30,000-fold selectivity over NTS1. Of particular importance, this macrocyclic analog is also able to potentiate the analgesic effects of morphine in a dose- and time-dependent manner. Exerting complementary analgesic actions via distinct mechanisms of nociceptive transmission, NTS2-selective macrocycles can therefore be exploited as opioid-free analgesics or as opioid-sparing therapeutics, offering superior pain relief with reduced adverse effects to pain patients.
阿片危机凸显了开发非阿片类替代药物来管理疼痛的迫切需求，这些药物需要具有有效、安全且无成瘾性的药物治疗特征。我们采用广泛的结构-活性关系方法，在此确定了一系列新型高度选择性的神经降压素受体 2（NTS2）大环化合物，它们在各种实验性疼痛模型中发挥强效、不依赖阿片类的镇痛作用。据我们所知，在该受约束的大环中，Ile 残基被环戊丙氨酸取代，Pro 和 Pro 被烯丙基甘氨酸取代，然后进行侧链到侧链环化，这是迄今为止针对 NTS2 鉴定出的最具选择性的类似物（K i 2.9 nM），对 NTS1 的选择性是 30,000 倍。特别重要的是，这种大环类似物还能够以剂量和时间依赖的方式增强吗啡的镇痛作用。通过不同的疼痛传递机制发挥互补的镇痛作用，因此，NTS2 选择性大环化合物可以作为无阿片类镇痛药或阿片类药物节约疗法来开发，为疼痛患者提供更好的疼痛缓解效果，同时减少不良反应。
