LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief

Lorella Pasquinucci,Carmela Parenti,Lorena Reina,Emilia Tomarchio,Rita Turnaturi,Zafiroula Georgoussi

doi:10.3390/molecules26144168

Abstract

Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule-multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described.

Highlights

In pain transmission the multitude and complexity of involved neuronal mechanisms provide several possible targets for pharmacological intervention [1]
The structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described
Neuropathic pain and post-herpetic neuralgia (PHN) relief may be evoked with local anesthetics such as the well-known lidocaine patch [4,5]

Summary

Introduction

In pain transmission the multitude and complexity of involved neuronal mechanisms provide several possible targets for pharmacological intervention [1]. The co-administration of a MOPr agonist and a DOPr. Molecules 2021, 26, 4168 agonist could produce antinociception with reduced side effects [29,30]. Dual-target ligands with MOPr/DOPr (delta opioid peptide receptor) agonist or MOPr agonist/DOPr antagonist activity showed an improved antinociception and a low propensity to develop side effects. DPI-3290 [31] (Figure 1), with a balanced MOPr/DOPr affinity profile and the ability to inhibit the contractility of electrically stimulated guinea pig ileum (GPI) and mouse vas deferens (MVD), produced a significant antinociceptive effect, totally and partially blocked by naloxone (NLX) and naltrindole (NTI), respectively. The MOPr agonist/DOPr antagonist UMB 425 [32] (Figure 1), subcutaneously (s.c.) administered, showed a significant antinociceptive effect. This review aims to point out the progress in the search for opioid multitarget ligands for persistent pain relief, with a focus on the dual-target MOPr/DOPr ligands LP1 and LP2. This review could represent a useful example of the discovery process of new opioid ligands with a safer profile

Dual-Target Benzomorphan-Based Ligands LP1 and LP2

In Vivo Pharmacological Evaluation

In Vitro Biological Evaluation

Findings

Conclusions