Dataset Information

Selective ? opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters.

ABSTRACT:

Background

Nor-BNI, GNTI and JDTic induce selective ? opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets.

Results

In binding assays, the three antagonists showed no detectable affinity (K(i)?10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for ? opioid receptors, with moderate selectivity over ? and ? (3 to 44-fold). Nor-BNI bound weakly to the ?(2C)-adrenoceptor (K(i)?=?630 nM). GNTI enhanced calcium mobilization by noradrenaline at the ?(1A)-adrenoceptor (EC???=?41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M? receptor antagonist (K(B)?=?3.7 µM). JDTic bound to the noradrenaline transporter (K(i)?=?54 nM), but only weakly inhibited transport (IC???=?1.1 µM). JDTic also bound to the opioid-like receptor NOP (K(i)?=?12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers.

Conclusions

Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of ?(1A)-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, ? opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective ? opioid antagonists.

SUBMITTER: Munro TA

PROVIDER: S-EPMC3747596 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters.

Munro Thomas A TA Huang Xi-Ping XP Inglese Carmela C Perrone Maria Grazia MG Van't Veer Ashlee A Carroll F Ivy FI Béguin Cécile C Carlezon William A WA Colabufo Nicola A NA Cohen Bruce M BM Roth Bryan L BL

PloS one 20130814 8

<h4>Background</h4>Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets.<h4>Results</h4>In binding assays, the three antagonists showed no detectable affinity (K(i)≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which ...[more]

PMID: 23976952

Similar Datasets

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.