Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors.

Kristina Puls,Helmut Schmidhammer,Mariana Spetea,Gerhard Wolber

doi:10.3390/molecules27030919

Kristina Puls, Helmut Schmidhammer + Show 2 more

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https://doi.org/10.3390/molecules27030919

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Abstract

Accumulated preclinical and clinical data show that peripheral restricted opioids provide pain relief with reduced side effects. The peripherally acting opioid analgesic HS-731 is a potent dual μ-/δ-opioid receptor (MOR/DOR) full agonist, and a weak, partial agonist at the κ-opioid receptor (KOR). However, its binding mode at the opioid receptors remains elusive. Here, we present a comprehensive in silico evaluation of HS-731 binding at all opioid receptors. We provide insights into dynamic interaction patterns explaining the different binding and activity of HS-731 on the opioid receptors. For this purpose, we conducted docking, performed molecular dynamics (MD) simulations and generated dynamic pharmacophores (dynophores). Our results highlight two residues important for HS-731 recognition at the classical opioid receptors (MOR, DOR and KOR), particular the conserved residue 5.39 (K) and the non-conserved residue 6.58 (MOR: K, DOR: W and KOR: E). Furthermore, we assume a salt bridge between the transmembrane helices (TM) 5 and 6 via K2275.39 and E2976.58 to be responsible for the partial agonism of HS-731 at the KOR. Additionally, we experimentally demonstrated the absence of affinity of HS-731 to the nociceptin/orphanin FQ peptide (NOP) receptor. We consider the morphinan phenol Y1303.33 responsible for this affinity lack. Y1303.33 points deep into the NOP receptor binding pocket preventing HS-731 binding to the orthosteric binding pocket. These findings provide significant structural insights into HS-731 interaction pattern with the opioid receptors that are important for understanding the pharmacology of this peripheral opioid analgesic.

Highlights

Opioid receptors are membrane-bound receptors belonging to the family of G proteincoupled receptors (GPCRs) [1]
We have reported previously on the specific binding of HS-731 to the three classical opioid receptors, MOR, DOR and KOR, in the rat brain and to the recombinant human receptors expressed in Chinese hamster ovary (CHO) cells (Table 1)
The MOR and DOR that did not exhibit TM5-TM6 ionic interactions, and were not forced to adopt an intermediate state conformation are able to be fully activated by the agonist HS-731.The present results highlight the importance of ionic interactions for the binding of the 6β-glycine substituted agonist HS-731 to the opioid receptors, and accentuate the non-conserved residue 6.58 and the N-terminus, as important selectivity determinants for the classical opioid receptors

Summary

Introduction

Opioid receptors are membrane-bound receptors belonging to the family of G proteincoupled receptors (GPCRs) [1]. The central role of the opioid system (opioid receptors and their endogenous and exogenous ligands) in pain treatment has been long recognized, with activation of each opioid receptor subtype leading to pain relief [2,3]. Because of their therapeutic relevance, the opioid receptors are among the few GPCRs determined in different activation states [4]. Diverse approaches in the design of safer analgesics include targeting multiple receptors simultaneously (bi- and multifunctional ligands) [11,12,13], functional selectivity at GPCRs (biased agonists) [11,14,15,16] and peripheralization of opioid receptor agonists [2,11,17,18]

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