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Structure of the human ?-opioid receptor in complex with JDTic.

ABSTRACT: Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of ?-opioid receptor (?-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human ?-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9?Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human ?-OR. Modelling of other important ?-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for ?-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human ?-OR.

SUBMITTER: Wu H

PROVIDER: S-EPMC3356457 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Structure of the human κ-opioid receptor in complex with JDTic.

Wu Huixian H Wacker Daniel D Mileni Mauro M Katritch Vsevolod V Han Gye Won GW Vardy Eyal E Liu Wei W Thompson Aaron A AA Huang Xi-Ping XP Carroll F Ivy FI Mascarella S Wayne SW Westkaemper Richard B RB Mosier Philip D PD Roth Bryan L BL Cherezov Vadim V Stevens Raymond C RC

Nature 20120321 7398

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of κ-opioid receptor (κ-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinit ...[more]

PMID: 22437504

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Project description:BackgroundNor-BNI, GNTI and JDTic induce ? opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the ? opioid receptor.MethodsTo evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS).ResultsIn each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of ? antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism.ConclusionsThe negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.

Dataset Information

Structure of the human ?-opioid receptor in complex with JDTic.

Publications

Structure of the human κ-opioid receptor in complex with JDTic.

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