ICI 174,864

Inverse agonistic effect of ICI-174,864 on the cloned delta-opioid receptor: role of G protein and adenylyl cyclase activation.[Pubmed:8967989]

Mol Pharmacol. 1996 Dec;50(6):1651-7.

Previous studies have established that the delta-selective antagonist ICI-174,864 exhibits negative intrinsic activity at the delta-opioid receptors in NG108-15 membranes. To determine whether ICI-174,864 can function as a true inverse agonist in intact cells, its ability to stimulate cAMP accumulation was examined in a human embryonic kidney 293 cell line (293/DOR) expressing the cloned murine delta-opioid receptor. Forskolin-stimulated cAMP accumulation in the 293/DOR cells was dose-dependently suppressed by the delta-selective agonist [D-Pen2, D-Pen5]enkephalin, and such inhibition was abolished by pertussis toxin or the opiate antagonist naloxone. In contrast, ICI-174,864 significantly potentiated the forskolin response. The ICI-174,864-induced enhancement of the forskolin response exhibited dose-dependency and was antagonized by [D-Pen2,D-Pen5]enkephalin and blocked by pertussis toxin. Neither ICI-174,864 nor pertussis toxin elevated the basal level of cAMP accumulation in the absence of forskolin. Other opiate antagonists, such as naloxone and naltrindole, were ineffective in enhancing the forskolin-stimulated cAMP accumulation. Elevation of cAMP levels in response to the activation of Gs (through either ligand-bound receptor or point mutation on alpha(s)) was also potentiated by ICI-174,864. Our results indicate that ICI-174,864 behaves as an inverse agonist in human embryonic kidney 293 cells stably expressing the delta-opioid receptor. The inverse agonistic effect of ICI-174,864 seemed to require Gi proteins and was clearly manifested when adenylyl cyclase was activated.

delta opioid receptor antagonist, ICI 174,864, is suitable for the early treatment of uncontrolled hemorrhagic shock in rats.[Pubmed:23838715]

Anesthesiology. 2013 Aug;119(2):379-88.

BACKGROUND: Fluid resuscitation is the essential step for early treatment of traumatic hemorrhagic shock. However, its implementation is greatly limited before hospital or during evacuation. The authors investigated whether delta opioid receptor antagonist ICI 174,864 was suitable for the early treatment of traumatic hemorrhagic shock. METHODS: With uncontrolled hemorrhagic-shock rats, the antishock effects of six dosages of ICI 174,864 (0.1, 0.3, 0.5, 1, 3, and 5 mg/kg) infused with or without a small volume of lactated Ringer's solution (LR) before bleeding controlled or bleeding cessation at different times were observed. RESULTS: ICI 174,864 (0.1-3 mg/kg) with or without 1/4 volume of LR infusion showed dose-dependent increase in the mean arterial blood pressure, and significantly prolonged the survival time and 8-h survival rate, as compared with ICI 174,864 plus 1/2 volume of LR infusion. The best effect was shown with 3 mg/kg of ICI 174,864. Bleeding cessation at 1, 2, or 3 h during infusion of ICI 174,864 (3 mg/kg) plus 1/4 volume of LR improved subsequent treatment (70% 24-h survival rate vs. 50 and 10% 24-h survival rate in hypotensive resuscitation and LR group, respectively). There was significant improvement in hemodynamic parameters, oxygen delivery, and tissue perfusion of hemorrhagic-shock rats with 3 mg/kg of ICI 174,864 plus 1/4 volume of LR infusion. CONCLUSION: delta Opioid receptor antagonist ICI 174,864 alone or with small volume of fluid infusion has good beneficial effect on uncontrolled hemorrhagic shock. Its early application can "buy" time for subsequent treatment of traumatic shock.

ICI 174,864, a selective delta opioid antagonist, reverses the learning impairment produced by [leu]enkephalin.[Pubmed:2153306]

Psychopharmacology (Berl). 1990;100(1):102-9.

The role of opioid delta receptors in the learning impairment produced by [leu]enkephalin (LE) in one-way active avoidance conditioning was investigated in mice. LE (30 and 100 micrograms/kg) impaired acquisition of the avoidance response, whereas ICI 174,864 (3.0 mg/kg), a selective delta opioid receptor antagonist, enhanced acquisition. The impairment produced by 100 micrograms/kg LE was completely reversed by 1.0 mg/kg ICI 174,864, a dose of the antagonist that by itself had no effect. Control studies provided evidence that the effects of ICI 174,864 and LE on conditioning cannot be explained by performance variables such as alterations in activity levels or footshock sensitivity. The results suggest that opioid delta receptors play an important role in the modulation of learning, and that the effects of LE on avoidance conditioning are mediated by delta receptors.

Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N,N-diallyl-tyrosine-Aib-phenylalanine-leucine, ICI 174,864 or naloxone in mice.[Pubmed:8388455]

J Pharmacol Exp Ther. 1993 May;265(2):633-40.

Previous studies showed that cannabinoids administered intrathecally (i.t.) produced antinociception and synergism with the antinociceptive effects of morphine. Low doses of naloxone that appear selective for the mu receptor failed to block the antinociceptive effect of the cannabinoids. The present studies evaluated the interaction of the cannabinoids with kappa and delta opioid antagonists and agonists. Antinociception produced by delta 9 tetrahydrocannabinol (THC) and delta 8-THC (i.v., ED80 doses) was blocked by the kappa antagonist, nor-BNI (10 and 20 micrograms/mouse). The effects of CP 55,940 administered i.v. were blocked by norbinaltorphimine (nor-BNI; i.v. but not i.t.). The delta antagonist, N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864; 10 micrograms/mouse administered i.t.), failed to block the effects of any of the cannabinoids administered i.v. Nor-BNI administered i.t. blocked the antinociception produced by the cannabinoids (administered i.t., ED80 doses). The AD50s generated for nor-BNI vs. i.t. administered delta 9-THC, delta 8-THC, levonantradol and CP 55,940 were 3.5, 1.1, 3.8 and 4.5 micrograms/mouse, respectively. Nor-BNI (10 micrograms/mouse i.t.) shifted the dose-effect curve for delta 9-THC to the right in a parallel manner. delta 9-THC was additive with the kappa agonist, U50,488H, whereas delta 9-THC produced a parallel 37-fold shift to the left in the dose-effect curve of the delta agonist, DPDPE. Nor-BNI (70 micrograms/mouse i.c.v.) or ICI 174,864 (10 micrograms/mouse i.t.) failed to block the effects of the cannabinoids administered i.t. The exact nature of the nor-BNI/cannabinoid interaction is yet to be determined.

Opioid agonist activity of ICI 174864 and its carboxypeptidase degradation product, LY281217.[Pubmed:2875170]

J Pharmacol Exp Ther. 1986 Sep;238(3):769-72.

The opioid peptide antagonist, ICI 174864 ([allyl]2-Tyr-alpha-amino-isobutyric acid (Aib)-Aib-Phe-Leu-OH), can produce analgesic effects in mice. The present study explored the possibility that ICI 174864 1) may have affinity and agonist efficacy at mu receptors and/or 2) may form a carboxypeptidase degradation product in vivo that possesses mu agonist activity. In vitro, ICI 174864 (10(-7) to 10(-4) M) inhibited the twitch in the electrically stimulated mouse vas deferens (ED50 = 90 microM) and guinea pig ileum (ED50 greater than 10(-4) M). The in vitro partial agonist activity of ICI 174864 was due to interaction with delta and not mu receptors because the apparent dissociation constant for naloxone using ICI 174864 as the agonist was similar to the apparent dissociation constant for the interaction of naloxone with delta and not mu receptors. Thus, ICI 174864 is a weak partial agonist at delta receptors with little affinity or efficacy at mu receptors. The incubation of ICI 174864 with carboxypeptidase A generated a peptide, LY281217 [(allyl)2-Tyr-Aib-Aib-Phe-OH], which was a more potent agonist in the mouse vas deferens and guinea pig ileum than ICI 174864. The agonist activity of LY281217 was due to interaction with mu and not delta receptors because LY281217 was approximately 100-fold more potent than ICI 174864 as an agonist in the guinea pig ileum, the apparent dissociation constant for naloxone using LY281217 as the agonist was similar to the apparent dissociation constant for the interaction of naloxone with mu receptors and the delta selective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies in vivo with ICI 174864 and [D-Pen2, D-Pen5]enkephalin.[Pubmed:2987731]

Neuropeptides. 1985 Feb;5(4-6):311-4.

We studied the in vivo pharmacology of a selective agonist (DPDPE) and a selective antagonist (ICI 174864) at delta opioid receptors. ICI 174864 (10 micrograms icv) caused postural abnormalities, barrel rotation and hypothermia in rats. DPDPE induced behavioural arousal (at 75 micrograms icv) and barrel rotation (at 125 micrograms) in rats. ICI 174864 (10 micrograms icv) attenuated acetic acid induced writhing in mice. This action was antagonized by naloxone (10 but not 2 mg/kg s.c.). A lower, non-agonist dose of ICI 174864 (5 micrograms) antagonized DPDPE (3 micrograms icv) in this test without affecting DAGO (0.0006 micrograms icv), a selective agonist at mu receptors. In the mouse tail flick test, ICI 174864 (10-50 micrograms icv) did not significantly antagonize the agonist actions of DPDPE (40 micrograms icv) or DAGO (0.3 micrograms icv). At 10-50 micrograms icv, ICI 174864 had no marked effect on gastrointestinal transit in mice. ICI 174864 (25 micrograms icv or 20 mg/kg s.c.) did not interact with mu opioid receptors in mice rendered physically dependent on morphine.

Studies in vitro with ICI 174,864, [D-Pen2, D-Pen5]-enkephalin (DPDPE) and [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO).[Pubmed:2987739]

Neuropeptides. 1985 Feb;5(4-6):383-6.

The interactions of a proposed, selective delta receptor antagonist (ICI 174,864) and selective agonists at mu and delta receptors, [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO) and [D-Pen2, D-Pen5]-enkephalin (DPDPE), respectively, have been studied using the electrically-stimulated mouse isolated vas deferens (MVD) and the guinea-pig isolated ileum (GPI). Incubation of increasing concentrations of ICI 174,864 (10,30,100 and 300 nM) produced a dose-related and parallel rightward displacement of the DPDPE dose-response curve in the MVD. In contrast, ICI 174,864 (300-3000 nM) failed to affect the DAGO dose-response curve in the same tissue. Analysis of the DPDPE-ICI 174,864 interaction in the MVD using the pA2 method revealed a Schild plot slope of -0.68 suggesting the involvement of more than one population of receptors. ICI 174,864 (300 nM) failed to antagonize DPDPE in the GPI at doses up to 30 microM. These results suggest that (a) ICI 174,864 acts as a selective delta antagonist in the MVD; (b) DPDPE interacts with mu receptors in the MVD but only at very high concentrations, and (c) delta receptors appear not to be of functional importance in the GPI.