Selective Κ-opioid Receptor Agonist Research Articles

Preparation and evaluation of some hydrophilic phenylacetyl-piperazines as peripherally selective κ-opioid receptor agonists

The synthesis of a series of hydrophilic phenylacetylpiperazines as potential peripherally selective κ-opioid receptor agonists is described. Several compounds were potent κ-agonists in vitro and one, the sulphone ( 18), showed significant peripheral selectivity in vivo .

Antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms

Morphine-induced antinociception was prevented by pretreatment with ginseng total saponins in the tail-pinch and tail-flick tests carried out in mice. The antinociceptive effect of U-50,488H, a selective κ-opioid receptor agonist, was prevented by naloxone, a nonselective opioid receptor antagonist, in the tail-pinch but not in the tail-flick test. However, U-50,488H-induced antinociception was prevented by ginseng total saponins in the tail-flick but not in the tail-pinch test. These results indicate that nonopioid mechanisms are involved in the antagonism of U-50,488H-induced antinociception by ginseng total saponins. In addition, the antagonism of U-50,488H-induced antinociception in mice pretreated with ginseng total saponins was abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan, but not by a noradrenaline precursor, L-dihydroxyphenylalanine, in the tail-flick test. Therefore, it appears that the antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.

Central monoaminergic mechanisms in mice and analgesic activity of spiradoline mesylate, a selective κ-opioid receptor agonist

We assessed the roles of brain monoaminergic systems in the analgesic action of spiradoline, a novel κ-opioid agonist, behaviorally and biochemically by using noradrenaline (NE) and serotonin (5-HT) uptake inhibitors. Analgesic activity was evaluated by measuring latency time in the mouse tail-pinch test. Spiradoline at intramuscular doses of 0.3 mg/kg or more elicited a significant analgesic effect and the metabolism of both NE and 5-HT was significantly increased in brainstem and cortex. Pretreatment of the mice with imipramine, desipramine or clomipramine caused marked otentiation of spiradoline analgesia, whereas reserpine and phenoxybenzamine inhibited it. Morphine analgesia was enhanced by clomipramine but not by imipramine, desipramine or phenoxybenzamine. These results suggest that excitation of noradrenergic and serotonergic pathways in the brain appears to be involved in spiradoline analgesia, and that, as regards tail-pinch nociception, the κ-opioid agonist acts on the noradrenergic pathway more potently than morphine.

A highly selective κ-opioid receptor agonist, CI-977, reduces excitatory synaptic potentials in the rat locus coeruleus in vitro

Intracellular recordings were made from neurons in a rat locus coeruleus slice preparation in vitro. A postsynaptic potential was evoked by electrical stimulation of afferents to the neurons. CI-977 ([5R-(5a,7a,8b)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzofuranacetamidemonohydrochloride) caused a depression of the evoked postsynaptic potential on locus coeruleus neurons. This action was reversed on washout. Bremazocine had a similar action on less than 50% of locus coeruleus neurons. Concentrations of CI-977 which depressed the postsynaptic potential did not affect either passive membrane conductance or a voltage-sensitive potassium current resembling I A. The depression of the excitatory postsynaptic potential caused by CI-977 remained in the presence of either 30 μM bicuculline and picrotoxin or when potassium acetate-filled recording electrodes were used. Using potassium chloride-filled recording electrodes and in the presence of 30 μM 6-cyano-2,3-dihydro-7-nitroquinoxaline-2,3-dione and either 30 μM dl-2-amino-5-phosphonovaleric acid or 500 μM kynurenic acid, CI-977 had no effect on the postsynaptic potential. The effects of CI-977 were reversed by 30–100 nM naloxone and 1–10 nM norbinaltorphimine but not by 1–10 nM naloxone. The hyperpolarizing response to the μ-opioid receptor-selective agonist d-Ala 2,Nme Phe 4,Gly-ol 5 (DAGOL) was blocked by 1–10 nM naloxone but not by 1–100 nM norbinaltorphimine. The hyperpolarizing response to DAGOL was not affected by high doses of CI-977. Doses of CI-977 1000–10,000 times higher than those which reduced the postsynaptic potentials had a naloxone-reversible hyperpolarizing action indistinguishable from that of DAGOL. Concentrations of bremazocine which reduced the excitatory postsynaptic potential antagonized the submaximal hyperpolarizing response to DAGOL. These results suggested that CI-977 acts as a potent agonist at a κ-opioid receptor located on presynaptic elements which release excitatory amino acids in the locus coeruleus. In contrast to CI-977, bremazocine acts as a weak agonist at these κ-opioid receptors and as a potent antagonist at μ-opioid receptors in the locus coeruleus.

Kappa-opioid modulation of vasopressin secretion in conscious rats.

A series of studies has been performed in the conscious rat to investigate the effect of the intracerebroventricular (i.c.v.) administration of the selective kappa-opioid receptor agonist, U50 488H, on arginine vasopressin (AVP) secretion stimulated by i.c.v. administration of hypertonic NaCl. Similarly, the effect of the i.c.v. administration of morphine and the i.v. administration of naloxone on AVP secretion was investigated. The response of AVP to an i.c.v. injection of hypertonic NaCl was potentiated by naloxone at a dose of 0.4 mg/kg, but a higher dose (1.2 mg/kg) was required to increase the basal plasma concentration of AVP. Prior treatment with U50 488H or morphine attenuated the increase in plasma concentrations of AVP stimulated by i.c.v. injection of hypertonic NaCl from 13.92 +/- 4.44 to 1.22 +/- 0.34 and 1.78 +/- 0.74 pmol/l respectively (n = 7; P less than 0.05). Prior administration of U50 488H also attenuated the potentiating effect of naloxone on AVP secretion stimulated by i.c.v. injection of hypertonic NaCl. These results indicate that basal AVP secretion is under tonic inhibitory control by dynorphin, and that mu- and kappa-opioid receptors mediate an inhibitory influence of endogenous opioids on osmoreceptor-mediated AVP secretion.

The anticonvulsant action of CI-977, a selective κ-opioid receptor agonist: a possible involvement of the glycine/NMDA receptor complex

The selective κ-opioid receptor agonist CI-977, stereoselectively antagonised clonic seizures induced by slow i.v. infusion of N-methyl-DL-aspartate in the mouse. It was found to be more efficacious and 10-fold more potent than the competitive N-methyl-D-aspartic acid receptor antagonist CPP (3-(±)-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid). The anticonvulsant action of CI-977 was antagonised by norbinaltorphimine, indicating a specific interaction with the κ-receptor. The effect of CI-977 but not that of CPP was also antagonised by the glycine/NMDA receptor agonist D-serine. These results provide evidence for a possible interaction between the κ-receptor and the glycine/NMDA receptor.

Attenuation of the antinociceptive action of the selective κ-opioid receptor agonist, U-50,488H by ICS-205-930

The antinociceptive action of s.c. administered U-50,488H was antagonized by s.c. administered ICS-205-930, a selective 5-HT3 receptor antagonist. To characterize the site of interaction, U-50,488H and ICS-205-930 were administered either intracerebroventricularly (i.c.v.) or intrathecally (i.t.). When U-50,488H was administered i.c.v., its antinociception action was antagonized by ICS-205-930 given either i.c.v. or i.t., increasing the ED50 values of U-50,488H by approximately twofold from 48 to 98 and 90 nmol/mouse, respectively. However, when U-50,488H was administered i.t., its antinociception action was not antagonized by ICS-205-930 given either i.c.v. or i.t. These findings suggest that i.c.v., but not i.t. administered U-50,488H may release serotonin both supraspinally and spinally to interact with 5-HT3 receptors to produce antinociception.

CI-977, A novel, selective and exceptionally potent kappa opioid agonist

Microdialysis was utilized to evaluate the effects of selective κ-opioid receptor agonists on dopamine levels in the dorsal caudate of conscious rats. Subcutaneous administration of equivalent antinociceptive doses of spiradoline -(±)-(5α,7α,8β)-3,4- dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]bennzeneacetamide - (U62066; 12 mg/kg), BRL 52656 - (2S)-1- [(4-triflouromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine - (2 mg/kg) and enadoline - (−)-(5β,7β,8α)-N-methyl-N- [7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide - (CI-977; 0.1 mg/kg) produced similar, statistically significant decreases in dorsal caudate dopamine levels; BRL 53001 - (2S)-2-(dimethylaminomethyl)-1-[5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine - (12 mg/kg) was, however, without effect. At a higher dose (36 mg/kg), BRL 53001 also caused a significant reduction in dopamine levels. BRL 52974 - 4-(1-pyrrolidinylmethyl)5-[(3,4-dichlorophenyl)acetyl]-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine , a selective κ-opioid receptor agonist with limited ability to cross the blood brain barrier or produce antinociceptive effects, had no effect on dopamine levels at 10 mg/kg s.c. Overall, these findings suggest that selective κ-opioid receptor agonists decrease dopamine levels in the dorsal caudate of rats via a central locus of action. Furthermore, compared to other κ-opioid receptor agonists, BRL 53001 appears to have a reduced propensity to decrease dopamine levels at equianalgesic doses.

Synthesis of an affinity ligand (‘UPHIT’) for in vivo acylation of the κ-opioid receptor

The isothiocyanate analog (1 S,2 S- trans-2-isothiocyanato-4,5-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, 3a) of the highly selective κ-opioid receptor agonist, U50,488, was prepared as a potential site-directed affinity ligand for acylation of κ-opioid receptors in vivo. The isothiocyanate ( 3a) which we have designated UPHIT and its enantiomer ( 3b) were synthesized in 3 steps starting from optically pure (1 S,2 S)-(+)- trans-2-pyrrolidinyl- N-methyl-cyclohexylamine ( 4a) and its enantiomer ( 4b), respectively, thus defining their absolute stereochemistry. Binding in vitro of the 1 S,2 S enantiomer 3a to κ receptors labelled by [ 3H]U69,593 was shown to occur with an IC 50 value of 25.92 ± 0.36 nM, whereas 827.42 ± 5.88 and 115.10 ± 1.23 nM were obtained for the IC 50 value of the 1 R,2 R enantiomer ( 3b) and (±)- 3 respectively. Intracerebroventricular (ICV) injection of 100 μg of (±)- 3 into guinea-pig brain followed by analysis of remaining κ-binding sites 24 h later revealed that (±)- 3 depleted 98% of the κ receptors that bind [ 3H]U69,593 and 40% of those that bind [ 3H]bremazocine. These preliminary data suggest exciting uses for these compounds in furthering our knowledge of the κ-opioid receptor.

The amygdala mediates the impairing effect of the selective κ-opioid receptor agonist U-50,488 on memory in CD1 mice

The effect of the selective κ-opioid receptor agonist U-50,488 on passive avoidance behaviour was studied in CD1 mice bearing lesions of the amygdaloid complex. The results have shown that post-trial injections of U-50,488 in unoperated mice as well as lesions of the amygdaloid complex in untreated mice decreased retention performances. No further impairment was observed in lesioned mice treated with U-50,488, indicating that amygdala is involved in the mediation of the effects of κ-opioid receptor agonists on memory. The possibility that κ-opioid receptors could modulate the memory retention of CD1 mice by influencing their emotional state is discussed.

Antagonism of μ-opioid receptor-mediated inhibitions of nociceptive neurones by U50488H and dynorphin A 1–13 in the rat dorsal horn

We have studied the effects of two highly selective κ-opioid receptor agonists, U50488H and dynorphin A 1–13 on the powerful inhibitions of rat dorsal horn nociceptive neurones produced by the potent μ-opiate receptor agonist, Tyr- d-Ala-Gly-Me-Phe-Gly-ol (DAGO). Extracellular single unit recordings were made from 35 convergent neurones which could be excited by impulses in Aβ- and C-fibre afferents following transcutaneous electrical stimulation of the ipsilateral hind paw. The μ- and κ-agonists were applied directly onto the surface of the spinal cord. DAGO (0.19, 0.48 and 1.9 nmol) dose-dependently inhibited C-fibre evoked responses with little effect on Aβ-evoked activity. The spinal application of dynorphin A 1–13 (6.2 nmol) and U50488H (28 nmol) rapidly reversed the spinal inhibitory effect of DAGO indicating that these κ-ligands are likely to act as μ-receptor antagonists in the rat dorsal horn.