Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA.
Molecules. 2019 Nov 26;24(23):4302. doi: 10.3390/molecules24234302.
The opioid receptors modulate a variety of biological functions, including pain, mood, and reward. As a result, opioid ligands are being explored as potential therapeutics for a variety of indications. Multifunctional opioid ligands, which act simultaneously at more than one type of opioid receptor, show promise for use in the treatment of addiction, pain, and other conditions. Previously, we reported the creation of bifunctional kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) partial agonist ligands from the classically delta opioid receptor (DOR) antagonist selective dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold through the addition of a 7-benzyl pendant on the tetrahydroisoquinoline ring. This study further explores the structure-activity relationships surrounding 7-position pendants on the Dmt-Tiq scaffold. Some analogues maintain a KOR agonist/MOR partial agonist profile, which is being explored in the development of a treatment for cocaine addiction. Others display a MOR agonist/DOR antagonist profile, which has potential to be used in the creation of a less addictive pain medication. Ultimately, we report the synthesis and in vitro evaluation of novel opioid ligands with a variety of multifunctional profiles.
阿片受体调节多种生物功能，包括疼痛、情绪和奖励。因此，阿片类配体被探索作为治疗多种适应症的潜在治疗方法。同时作用于一种以上阿片受体的多功能阿片类配体有望用于治疗成瘾、疼痛和其他疾病。此前，我们报道了从经典的δ阿片受体（DOR）拮抗剂选择性二甲基酪氨酸-四氢异喹啉（Dmt-Tiq）支架中通过在四氢异喹啉环上添加 7-苄基侧链来创建双功能κ阿片受体（KOR）激动剂/μ阿片受体（MOR）部分激动剂配体。本研究进一步探讨了 Dmt-Tiq 支架 7 位取代基周围的结构-活性关系。一些类似物保持 KOR 激动剂/MOR 部分激动剂特性，正在探索用于治疗可卡因成瘾的方法。其他类似物显示出 MOR 激动剂/DOR 拮抗剂特性，有可能用于开发成瘾性较低的止痛药物。最终，我们报告了具有多种多功能特性的新型阿片类配体的合成和体外评价。
