Abstract
BackgroundNor-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.ResultsIn 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 κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α2C-adrenoceptor (K i = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α1A-adrenoceptor (EC50 = 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 M1 receptor antagonist (K B = 3.7 µM). JDTic bound to the noradrenaline transporter (K i = 54 nM), but only weakly inhibited transport (IC50 = 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.ConclusionsAcross 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α1A-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, κ 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 κ opioid antagonists.
Highlights
Selective k opioid antagonists may have therapeutic potential against conditions such as depression and anxiety disorders [1,2]
Duration of action is extremely long; while competitive antagonists are typically effective for only hours or at most days, k antagonism can persist for weeks or months after nor-BNI, GNTI or JDTic [4]
We found there that nor-BNI and GNTI were not substrates of human permeability glycoprotein (P-gp); taken together our results suggest that these antagonists may be substrates of another efflux transporter
Summary
Selective k (kappa) opioid antagonists may have therapeutic potential against conditions such as depression and anxiety disorders [1,2]. Duration of action is extremely long; while competitive antagonists are typically effective for only hours or at most days, k antagonism can persist for weeks or months after nor-BNI, GNTI or JDTic [4]. To account for this abnormal timecourse, it was long presumed that these compounds were slowly absorbed and eliminated. Studies have suggested instead that norBNI, GNTI and JDTic activate the enzyme c-Jun N-terminal kinase 1 (JNK1, MAPK8), causing desensitization of k-OR that persists long after the compounds are eliminated [5] These compounds appear to induce functional antagonism via a noncompetitive mechanism. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets
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