title: Selective κ 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 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.
  
  
  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 κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α(2C)-adrenoceptor (K(i) = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α(1A)-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.
  
  
  CONCLUSIONS
  Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α(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, 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.
authors: McLean Hospital, Belmont, Massachusetts, United States of America ; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America ; School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, Australia.
authors: Thomas A
authors: TA
authors: Munro
authors: Xi-Ping
authors: XP
authors: Huang
authors: Carmela
authors: C
authors: Inglese
authors: Maria Grazia
authors: MG
authors: Perrone
authors: Ashlee
authors: A
authors: Van't Veer
authors: F Ivy
authors: FI
authors: Carroll
authors: Cécile
authors: C
authors: Béguin
authors: William A
authors: WA
authors: Carlezon
authors: Nicola A
authors: NA
authors: Colabufo
authors: Bruce M
authors: BM
authors: Cohen
authors: Bryan L
authors: BL
authors: Roth
mesh_terms: D000494:Allosteric Regulation; D001692:Biological Transport; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009019:Morphinans / Q000378:metabolism* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D006146:Guanidines; D009019:Morphinans; D009292:Narcotic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; D011942:Receptors, Adrenergic, alpha; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C051844:norbinaltorphimine; D009271:Naltrexone; D002118:Calcium; D009638:Norepinephrine
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