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Papers of the Week


Papers: 6 Feb 2021 - 12 Feb 2021


Animal Studies, Pharmacology/Drug Development


2021 Feb 08


Elife


10

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site.

Authors

Uprety R, Che T, Zaidi SA, Grinnell SG, Varga BR, Faouzi A, Slocum ST, Allaoa A, Varadi A, Nelson M, Bernhard SM, Kulko E, Le Rouzic V, Eans SO, Simons CA, Hunkele A, Subrath J, Pan Y X, Javitch JA, McLaughlin JP, et al.
Elife. 2021 Feb 08; 10.
PMID: 33555255.

Abstract

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.