SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity.
Linghui KongXuelian ShuSiyuan TangRongrong YeHuijiao SunShuang JiangZixiang LiJingrui ChaiYun FangYinjie LanLinqian YuQiong XieWei FuYujun WangWei LiZhuibai QiuJinggen LiuLiming ShaoPublished in: Journal of medicinal chemistry (2022)
Undue central nervous system (CNS) side effects including dysphoria and sedation remain to be a challenge for the development of κ opioid receptor (KOR) agonists as effective and safe analgesics. On the basis of our previous work on morphinan-based KOR agonists, a series of 7α-methyl-7β-substituted northebaine derivatives were designed, synthesized, and biologically assayed. Among others, compound 4a ( SLL-627 ) has been identified as a highly selective and potent KOR agonist both in vitro and in vivo , and its molecular basis was also examined and discussed. Besides low liability to conditioned place aversion (CPA) test, treatment of SLL-627 was associated with a nonreduction in locomotor activity, compared to most of the other arylacetamide- or morphinan-based KOR agonists which generally exhibited apparently sedative effects. This unexpected finding provides new insights to dissociate analgesia from sedation for future discovery of innovative KOR agonists.
Keyphrases
- molecular docking
- molecular dynamics simulations
- pain management
- spinal cord injury
- chronic pain
- small molecule
- mechanical ventilation
- high throughput
- blood brain barrier
- anti inflammatory
- current status
- intensive care unit
- binding protein
- single cell
- acute respiratory distress syndrome
- extracorporeal membrane oxygenation