Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective μ Opioid Receptor Agonists

Pain was implicated in many diseases. Despite effectiveness to treat moderate to severe pain, opioid analgesics elicited many side effects, greatly limiting their prescription in clinics. Based on Ml, an active metabolite of tramadol, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-4-ol analogues were designed, synthesized, and evaluated in vitro. Among all the compounds tested, compound 23 was found to be a novel, highly selective, and potent MOR agonist (K-i (MOR) = 0.0034 nM, EC50 MOR = 0.68 nM, E-max = 206.5%; K-i (DOR) = 41.67 nM; K KOR = 7.9 nM). Structure-activity relationship exploration showed that the linker between the piperidine ring and the phenyl ring as well as substituent pattern of the phenyl ring played a pivotal role in binding affinity and selectivity. (3R, 4S)-23 (K-i (MOR )= 0.0021 +/- 0.0001 nM, EC50 (MOR) = 0.0013 +/- 0.0001 nM, E-max = 209.1 +/- 1.4%; K DoR = 18.4 +/- 0.7 nM, EC50 (DOR) = 74.5 +/- 2.8 nM, E-max= 267.1 +/- 1.4%; K-i (KOR) = 25.8 +/- 0.2 nM, EC50 (DOR) = 116.2 +/- 4.4 nM, E-max = 209.5 +/- 1.4%) had more potent activity for opioid receptors than its enantiomer (3S, 4R)-23 and was found to be a potent, highly selective MOR agonist with novel scaffold. High binding affinity and selectivity of (3R, 4S)-23 for MOR over KOR and DOR and its mechanism of activating MOR were proposed by docking and molecular dynamics simulations, respectively.

Automated summary

Pain is associated with many diseases, and opioid analgesics are effective but have limitations due to side effects. A study focused on designing and synthesizing novel analogues based on an active metabolite of tramadol, leading to the discovery of compound 23 as a potent and highly selective MOR agonist. Structure-activity relationship exploration revealed that the linker and substituent pattern play a crucial role in binding affinity and selectivity.