Molecular basis of opioid receptor signaling

Abstract

Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Advancements in structural, molecular, and computational tools illuminate the dynamic interplay between opioids and opioid receptors, as well as the molecular determinants of signaling pathways, which are potentially interlinked with pharmacological responses. Here, we review the molecular basis of opioid receptor signaling with a focus on the structures of opioid receptors bound to endogenous peptides or pharmacological agents. These insights unveil specific interactions that dictate ligand selectivity and likely their distinctive pharmacological profiles. Biochemical analysis further unveils molecular features governing opioid receptor signaling. Simultaneously, the synergy between computational biology and medicinal chemistry continues to expedite the discovery of novel chemotypes with the promise of yielding more efficacious and safer opioid compounds.

Figure 1.. An overview of the actions of opioids.

Opioid signaling is initiated from the binding of different types of neurotransmitters or synthetic small molecules to the opioid receptors on the cell membrane. The cascade is then propagated by the activation of intracellular G proteins and arrestins. Depending on the location of cells/neurons that express the opioid receptors, different behavioral responses are observed. The question mark under nociceptin receptor (NOPR) indicates currently incomplete understanding of adverse effects from NOPR agonists. Typical adverse effects from DOR, MOR, and KOR are not observed from NOPR agonists.

Figure 2.. Opioid and opioid receptor mediated signaling pathways.

A. Phylogenetic tree of classic opioid receptors and atypical opioid receptors. A common feature is that all of them could be activated by small peptides and small-molecule opioids, consistent with the evolutionary distance compared with other class A, B, F GPCRs. OPRD1 (DOR), OPRM1 (MOR), OPRK1 (KOR), OPRL1 (NOPR), ACKR3 (CXCR7), MRGX1-4 (MRGPRX1-4). B. Conventional downstream signaling of opioid receptor activation: G protein pathway and G protein independent pathway. Note that GRKs and β-arrestins activation can be mediated by active receptor without precoupled G protein activation (G protein inde[endent pathway) or by active receptor subsequent of G protein activation (G protein dependent pathway). C. Sequence alignment of diverse signaling transducers, Gαi/o, GRK, and β-arrestin subtypes.

Figure 3.. Diverse ligand-binding poses in atypical MRGPRX receptors.

A-B. The binding poses of BAM8-22, Cortistatin-14, or MS47134 at MRGPRX1, MRGPRX2, or MRGPRX4, respectively. C-D. Structures of MRGPRX2-Gi1 complex bound to Zin3573, C48, or Substance P, respectively.

Figure 4.. Binding poses of endogenous ligands at four opioid receptors.

A. The binding poses of endogenous peptides at opioid receptors. Amino acid sequence is shown for each peptide. The anchoring residue D3.32 is shown. B. Sequence alignment of highly diverse extracellular loops (ECLs) from four human opioid receptors. C. Sequence alignments of highly conserved intracellular loops (ICLs). Different colors represents the subclasses of residues.

Figure 5.. Binding poses of small molecule ligands at four opioid receptors.

A. The binding poses of naturally occurring opioids at opioid receptors. Note that MOR/Mitragynine has two binding poses that are not distinguishable from the density map. B. The binding poses of highly abusing ligands fentanyl and lofentanil. C. Comparison of binding poses between morphine and fentanyl or fentanyl and lofentanyl reveals extra binding pockets and interactions. D. The binding poses of therapeutically potential ligands. Oliceridine (TRV130).

Figure 6.. Structural determinants of ligand selectivity and signal transducers.

A. Structural motifs responsible for ligand selectivity, potency/efficacy, and signal transducer selectivity, respectively. B. Comparison of extracellular loops (ECLs) and intracellular loops (ICLs) between different opioid receptors.