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Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes.

ABSTRACT: 1. Taking advantage of the functional coupling of the opioid receptors with the G-protein-activated K+ (GIRK) channel, we investigated the effects of sigma (sigma) ligands of various structural and pharmacological classes, (+)-N-allylnormetazocine ((+)-SKF10047) and (+)-cyclazocine, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), 1,3-di-(2-tolyl)guanidine (DTG), carbetapentane and haloperidol, on the inward K+ current responses in Xenopus oocytes co-injected with each of the cloned mu-, delta- and kappa-opioid receptor mRNAs and the GIRK1 mRNA. 2. (+)-SKF10047 acted as a delta- and kappa-agonist (EC50 values (microM) = 0.618 and 0.652, respectively) and mu-antagonist (IC50 value (microM) = 8.51). (+)-Cyclazocine acted as a kappa-agonist and mu-antagonist (IC50 = 33.2). (+)-3PPP acted as a kappa-agonist (EC50 = 18.08 and a mu-antagonist. DTG acted as a mu- and kappa-agonist (EC50 = more than 30 and 14.88, respectively). Carbetapentane acted as a kappa-agonist and mu-antagonist (IC50 = 11.2). Haloperidol acted as a mu- and delta-agonist (EC50 = 5.683 and 7.389, respectively). 3. All currents induced by sigma ligands were reduced by 1 microM naloxone, an opioid receptor antagonist, and blocked by 300 microM Ba2+, a GIRK channel blocker. It was also indicated that the antagonism by naloxone at the delta-- and kappa-opioid receptors was weaker than that of naloxone at the mu-opioid receptor. The sigma ligands tested had no effect on the current responses in the oocytes injected with each of the opioid receptor mRNAs alone or with the GIRK1 mRNA alone. 4. We conclude that various sigma ligands directly interact with the cloned mu-, delta- and kappa-opioid receptors in Xenopus oocytes. Our results suggest that the effects of the sigma ligands may be partly mediated by the opioid receptors.

SUBMITTER: Kobayashi T

PROVIDER: S-EPMC1915734 | biostudies-literature | 1996 Sep

REPOSITORIES: biostudies-literature

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Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes.

Kobayashi T T Ikeda K K Ichikawa T T Togashi S S Kumanishi T T

British journal of pharmacology 19960901 1

1. Taking advantage of the functional coupling of the opioid receptors with the G-protein-activated K+ (GIRK) channel, we investigated the effects of sigma (sigma) ligands of various structural and pharmacological classes, (+)-N-allylnormetazocine ((+)-SKF10047) and (+)-cyclazocine, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), 1,3-di-(2-tolyl)guanidine (DTG), carbetapentane and haloperidol, on the inward K+ current responses in Xenopus oocytes co-injected with each of the cloned mu ...[more]

PMID: 8872359

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Project description:The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a known pharmacophore for mu opioid (MOP), kappa opioid (KOP), and delta opioid (DOP) receptor antagonists; however, it has not been explored in nociceptin opioid (NOP/ORL-1) receptor ligands. We recently found that the selective KOP antagonist JDTic, (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide, containing this opioid antagonist pharmacophore, has significant binding affinity at the NOP receptor (Ki 16.67 ± 0.76 nM), with no intrinsic activity in the [(35)S]GTPγS functional assay. Since this is the first ligand containing the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore to have affinity for the NOP receptor, we explored the structural determinants of its NOP binding affinity. When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic. Interestingly, however, removal of the 3,4-dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold of JDTic increased the binding affinity at NOP by 10-fold (Ki 1.75 ± 0.74 nM) while maintaining comparable affinity for KOP, MOP, and DOP receptors (Ki 1.14 ± 0.63, 1.67 ± 0.6, and 19.6 ± 1.3 nM, respectively). In vitro functional efficacy studies using the [(35)S]GTPγS assay showed that this compound AT-076 functions as an antagonist at all four opioid receptors. Detailed characterization of the antagonist activity of AT-076 shows that it has a noncompetitive antagonist profile at the NOP and KOP receptors (insurmountable antagonism), but is a potent competitive antagonist at the MOP and DOP receptors, with Ke values 3-6-fold more potent than those of JDTic. AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes. Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076.

Dataset Information

Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes.

Publications

Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes.

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