Analgesis, Addiction Studies And Molecular Modelling Of Three Endomorphin Analogs

Endomorphin-1(EM-1, Tyr-Pro-Trp-Phe-NH₂) and endomorphin-2(EM-2, Tyr-Pro-Phe-Phe-NH2) are two endogenous opioid peptides with high affinity and selectivity for mu-opioid receptors (MOR) and have extensive pharmacological effects especially mediate high potent analgesis effects. Since theμ-opioid receptors mediate the most prominent pharmacological effects of morphine, endomorphins are important model peptides in the search toward new analgesics. But treatment of pain with opioids is limited by their potential abuse liability. In an effort to develop analgesics without this side effect, an unbiased conditioned place preference(CPP) paradigm was used to evaluate the reward effect of endomorphins and their analogs . In this paper, we focused on the anlagesis and CPP relationship studies of endomorphins and their analogs, and tried to give some possible explainations for the mechanism by the molecular modeling study.Pre- and post-conditioning free-movement were measured on day 1 and day 5, respectively. Conditioning sessions were conducted twice daily from day 2 through day 4 consisting of the alternate injection of conditioning drug or vehicle. Intracerebroventricular (i.c.v.) injection of endomorphin-1 (0.5-6 nmol/kg) induced place preference in a dose-dependent manner; whereas, [D-V⁴-Bzl]EM1(6.67nmol/kg, icv, 50% MPE) produced significant analgesic effects, however, it failed to show reward properties in the standard 45- min conditioned place preference (CPP) paradigm. But endomorphin-2 (1-5 nmol/kg) dose-dependently induced conditioned place aversion (CPA) . EM-2 analogs Tyr-Pro-(L-aminoxy Phe)-PheNH2 and Tyr-Pro-(D-aminoxy Phe)-PheNH2(5-20nmolkg^-1), with N-0 turn structures at the Pro2-aminoxy-Phe3 position, had low antinociceptive efficacy and didn't induce CPA.To further investigate the structure characteristics, which may have great influence on the binding procedure and activation mechanism, of our analogs, we've used the ligand docking and molecular dynamic simulation (MDS) methods to explore these features. By our computational studies, we found that the ligand with higher affinity tend to adopt the more extended conformation which may facilitate the interactions, like hydrogen-bond and aromatic contact, between the ligand and the receptor. And we also found some common movements concerning the trans-membrane (TM) region 3, 4, 5 and 6 of the receptor when bound with our ligands.