Designing Safer Analgesics via μ-Opioid Receptor Pathways

Abstract

Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics.

Keywords: GPCR; computational biology; drug discovery; opioid receptor; safer painkiller.

Figure I

Targets Involved in Modern Nociception and Analgesia Drug Design. (A) Peripheral targets including Kv, Nav, Cav, TRP, P2X, and GPCRs. (B) Their locations in the dorsal horn and periphery. (C) Dorsal horn targets including opioid, serotonin, cannabinoid, GABA, and NMDA receptors.

Figure I

The GPCR Family. (A) The phenotypic tree of GPCRs composed of five different families. White circles, GPCRs without crystal structures. Red circles, GPCRs with crystal structures. (B) Structures of different GPCR classes.

Figure 1

Signaling Pathways of the μ-Opioid Receptor (μOR). μOR can activate the heterotrimeric G protein, G_i. G protein-coupled receptor kinases (GRKs) together with protein kinases C (PKCs) catalyze the phosphorylation of agonist-bound receptors, which can subsequently either bind to arrestin, undergo internalization, or signal through MAP kinase and other pathways. μORs exhibit basal agonist-independent activation of G_i. Molecules that can suppress basal activity are called inverse agonists [9,46]. Neutral antagonists block the binding of other ligands without imposing a biological response. There are two categories of agonists: full agonists and partial agonists [9,46]. Full agonists produce a full biological response whereas partial agonists only produce a partial biological response even at saturating concentrations [9,46]. These properties are independent of ligand affinities.

Figure 2

Activation Mechanism of the μ-Opioid Receptor (μOR). (A) Superimposed structures of inactive μOR (grey cartoon) and activated μOR (green cartoon). Transmembrane helices (TM) V, VI, and VII undergo unique movements upon agonist binding. (B) Molecular switches in the orthosteric site at the extracellular region. (C) Binding modes of the antagonist β-FNA (grey ball-and-stick) and agonist BU72 (green ball-and-stick). β-FNA forms a tight stacking interaction with highly conserved W293^6.48, whereas BU72 leaves a large void in the orthosteric site (yellow circle). (D) Molecular switches in the intracellular region. (E) Rearrangements of the PIF core. Left, antagonist-bound μOR; right, agonist-bound μOR.