Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Ewa Witkowska,Paweł K Halik,Katarzyna Kosińska,Barbara Przewlocka,Jowita Osiejuk,Anna Piotrowska,Piotr F J Lipiński,Joanna Matalińska,Magda Godlewska,Aleksandra Misicka,Beata Wileńska,Sandra Gątarz,Jolanta Dyniewicz,Ewa Gniazdowska,Joanna Starnowska-Sokół

doi:10.3390/ijms23020674

Abstract

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

Highlights

IntroductionNeuropathic pain results from a damage or from a disease of the nervous system [1]
Opioids are usually used in acute pain therapy with satisfying outcomes, but they are disappointingly ineffective in neuropathic pain
On the basis of these premises, and on the basis of our previous in-depth studies that dealt with the involvement of the melanocortin-4 receptor in pain transmission [16,17], the molecules we designed consist of two pharmacophores: an opioid agonist connected by a linker with a melanocortin-4 (MC4) receptor antagonist

Summary

Introduction

Neuropathic pain results from a damage or from a disease of the nervous system [1] This particular type of pain often becomes chronic and drugs in current medicinal use have limited effect on it. The use of conventional opioid agonists for the treatment of chronic pain with neuropathic component is limited due to their weaker analgesic effects and the potential occurrence of undesirable side effects such as constipation, respiratory depression, tolerance, and dependence [2,3,4,5]. After the first post-injury period, when the endogenous antinociceptive (opioid) system is activated, other endogenous systems come into play as counteractants of the elicited opioid activity These systems constipation, respiratory depression, tolerance, and dependence [2,3,4,5]. These systems generate pronociceptive compounds that exert their of effect through non-opioid receptors and weaken the effect of analgesics [5]

Methods

Results

Conclusion