nalorphine and bremazocine

Topics: Analgesics; Animals; Behavior, Animal; Benzomorphans; Cyclazocine; Discrimination Learning; Dogs; Dopamine; Drug Tolerance; Electroencephalography; Humans; Macaca mulatta; Mice; Morphine; Morphine Dependence; Motor Activity; Nalorphine; Pain; Rabbits; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Temperature

Human kappa opioid receptor (κ-OR), a G protein-coupled receptor (GPCR), has been identified as a drug target for treatment of such human disorders as pain perception, neuroendocrine physiology, affective behavior, and cognition. In order to find more selective and active agonists, one would like to do structure based drug design. Indeed, there is an X-ray structure for an antagonist bound to κ-OR, but structures for activated GPCRs are quite different from those for the inactive GPCRs. Here we predict the ensemble of 24 low-energy structures of human kappa opioid receptor (κ-OR), obtained by application of the GEnSeMBLE (GPCR Ensemble of Structures in Membrane Bilayer Environment) complete sampling method, which evaluates 13 trillion combinations of tilt and rotation angles for κ-OR to select the best 24. To validate these structures, we used the DarwinDock complete sampling method to predict the binding sites for five known agonists (ethylketocyclazocine, bremazocine, pentazocine, nalorphine, and morphine) bound to all 24 κ-OR conformations. We find that some agonists bind selectively to receptor conformations that lack the salt bridge between transmembrane domains 3 and 6 as expected for active conformations. These 3D structures for κ-OR provide a structural basis for understanding ligand binding and activation of κ-OR, which should be useful for guiding subtype specific drug design.

Topics: Benzomorphans; Binding Sites; Drug Design; Ethylketocyclazocine; Humans; Ligands; Models, Molecular; Molecular Docking Simulation; Morphine; Nalorphine; Pentazocine; Protein Conformation; Receptors, G-Protein-Coupled; Receptors, Opioid, kappa; Structure-Activity Relationship

Recent studies indicate that sex and rodent strain are determinants of sensitivity to opioid-induced antinociception.. The present study examined the influence of sex and rat strain on kappa opioid-induced antinociception using a series of kappa opioids that vary in their relative effectiveness.. In a warm-water (50, 52 and 55C) tail-withdrawal procedure, the antinociceptive effects of kappa opioids were determined in male and female rats of the F344, Lewis and Sprague-Dawley (SD) strains.. In both males and females of each strain, spiradoline produced high levels of antinociception across all nociceptive stimulus intensities, whereas U50,488 produced high levels only at the low and moderate nociceptive stimulus intensities. Sex differences in the potency and effectiveness of these kappa opioids were relatively small and not consistently obtained. Enadoline, bremazocine and nalorphine were less effective than spiradoline in producing antinociception, and at low and moderate nociceptive stimulus intensities these opioids were both more potent and effective in F344 and SD males than their female counterparts. In contrast, in Lewis rats, only bremazocine was more potent and effective in males. In combination tests, bremazocine shifted the spiradoline dose-effect curve leftward and/or upward in males and rightward in females (i.e., antagonized spiradoline). In contrast, in both males and females enadoline shifted the spiradoline dose-effect curve leftward and/or upward.. These data indicate that kappa opioids were generally more potent and effective as antinociceptive agents in males than females. Similar to data obtained with micro opioids, the magnitude of these sex differences was generally larger with the less effective kappa opioids and determined, in part, by rat strain and nociceptive stimulus intensity.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzofurans; Benzomorphans; Female; Male; Nalorphine; Narcotics; Pyrrolidines; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sex Characteristics

Eight kappa-opioid receptor agonists were examined for their effects in squirrel monkeys responding under a fixed interval 3-min schedule of stimulus termination. Six of these kappa-opioid receptor agonists decreased dose-dependently the total number of responses and with an order of potency consistent with kappa-opioid receptor interaction. Three of these kappa-opioid receptor agonists, bremazocine, U69,593 [[(5a,7a,8b)-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)] benzeneacetamide] and enadoline, were evaluated following pretreatment with 1.0 mg/kg of naltrexone or 3.0 mg/kg of norbinaltorphimine. The effects of the three agonists were antagonized significantly by naltrexone, but only those of bremazocine and U69,593 were antagonized significantly by norbinaltorphimine. Statistical analysis of the data averaged over six monkeys revealed that naltrexone was significantly more potent than norbinaltorphimine at antagonizing enadoline and U69,593, but naltrexone and norbinaltorphimine were equipotent at antagonizing bremazocine. Moreover, naltrexone was 8-fold more potent at antagonizing U69,593 and enadoline than at antagonizing bremazocine. These results suggest that under these conditions the effects of U69,593 and enadoline may be mediated, in part, by a different receptor population, perhaps a subtype of kappa-opioid receptors, from the one that mediates the effects of bremazocine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Behavior, Animal; Benzeneacetamides; Benzofurans; Benzomorphans; Conditioning, Operant; Dose-Response Relationship, Drug; Ethylketocyclazocine; Nalorphine; Naltrexone; Narcotic Antagonists; Pyrroles; Pyrrolidines; Receptors, Opioid, kappa; Reinforcement Schedule; Saimiri; Thiophenes

Marked diuresis has previously been reported after administration of kappa opioid agonists. The present study shows that this effect is stereospecific; MR-2034 markedly increased urinary output over the dose range 0.08 to 1.25 mg/kg, whereas the opposite isomer, MR-2035, was markedly less potent. Bremazocine increased urinary output in Long-Evans hooded and Sprague-Dawley albino rats as well as lean and fatty Zucker rats. In the lean Zucker and the albino rats, bremazocine produced an inverted U-shaped diuretic dose-effect curve, an effect characteristic of kappa agonists with mu agonist activity. This pattern was not seen with the fatty Zucker rats or the Long-Evans hooded rats. The full kappa agonists bremazocine, ethylketazocine and U-50,488 increased urinary output under three different conditions of hydration: water loaded, normal hydration and water deprived. In contrast, the partial kappa agonists reliably only increase urinary output under the normal hydration condition. The diuretic effects of full and partial kappa agonists correlated with plasma vasopressin levels in water-deprived rats. The full kappa agonists (ethylketazocine, U-50,488, tifluadom and MR-2034) suppressed plasma vasopressin levels below the threshold of detectability of the radioimmunoassay, whereas the partial kappa agonists (nalorphine and butorphanol) suppressed vasopressin levels compared with control values but did not have the efficacy of the full kappa agonists. All these results support the hypothesis that kappa agonists produce their diuretic effect by suppression of plasma vasopressin levels.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Butorphanol; Cyclazocine; Diuresis; Drinking; Ethylketocyclazocine; Female; Male; Nalorphine; Pyrrolidines; Rats; Rats, Inbred Strains; Rats, Zucker; Receptors, Opioid; Receptors, Opioid, kappa; Stereoisomerism; Vasopressins; Water Deprivation

The proposed kappa opioid receptor agonists ethylketocyclazocine (EK), nalorphine, bremazocine and U-50,488H were evaluated for their ability to produce contractions of isolated, vascularly perfused canine small intestinal segments. Responses to these agonists were compared to those of morphine and phenazocine, a mu benzomorphan. Morphine (0.04-25 micrograms) and phenazocine (0.01-3.0 micrograms) both produced naloxone-reversible contractions, suggesting that the responses were mediated largely by mu opioid receptors. In contrast, the proposed kappa agonists were ineffective in producing intestinal stimulation, with only EK (1-100 micrograms) showing minimal but significant activity at very high doses. We suggest that the effects of EK may be mediated through mu opioid receptors and that kappa receptors appear not to be involved in the contractile response of the dog small intestine to opioids.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzomorphans; Cyclazocine; Dimethylphenylpiperazinium Iodide; Dogs; Ethylketocyclazocine; Gastrointestinal Motility; In Vitro Techniques; Intestine, Small; Morphine; Nalorphine; Phenazocine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The purpose of this study was to investigate further the kappa opioid receptor selectivity of the field-stimulated isolated rabbit vas deferens preparation and to study the profile of a series of kappa agonists in this tissue. Agonists acting at mu, delta and sigma receptors were without detectable effect in the rabbit vas deferens. But a number of kappa agonists, including bremazocine, tifluadom, ethylketocyclazocine, ketocyclazocine, U-50,488 and Win 42,610 all depressed contractions, producing parallel dose-response curves. Mr 2034 generally produced a shallower dose-response curve and achieved a lower maximum effect, thus acting like a partial agonist. The effect of ethylketocyclazocine was not reduced by the irreversible mu antagonist, beta-funaltrexamine, confirming that it is not acting via mu receptors. Another group of drugs, including nalorphine, butorphanol and proxorphan, which produce an agonist action via kappa receptors in the guinea-pig ileum and mouse vas deferens, were antagonists in the rabbit vas deferens, suggesting that this tissue will only respond to high efficacy kappa agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Cyclazocine; Ethylketocyclazocine; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Nalorphine; Naloxone; Pyrrolidines; Rabbits; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vas Deferens

The discriminative stimulus properties of nalorphine were studied in rhesus monkeys trained to discriminate i.m. injections of nalorphine (1 mg/kg) from saline. During training, a two-lever paradigm was employed where a single, 3-min extinction schedule was followed by fixed-ratio-20 schedules of food presentation. During the fixed-rate schedules, responses on one of the two levers produced food when nalorphine had been administered and responses on the other lever produced food when saline had been administered. During stimulus generalization tests, responses on either lever produced food under the fixed-ratio schedule. The discriminative stimulus effects of nalorphine were antagonized by naloxone which, by itself, did not generalize to nalorphine. The kappa opiate agonists, ethylketocyclazocine, U-50,488, bremazocine, tifluadom, as well as two mixed kappa-sigma agonists, dl-cyclazocine and dl-N-allylnormetazocine (SKF-10047), generalized to nalorphine with the following potency ranking order: bremazocine greater than ethylketocyclazocine greater than tifluadom greater than cyclazocine greater than U-50,488 greater than N-allylnormetazocine greater than nalorphine. The levo-isomers of cyclazocine, N-allylnormetazocine or U-50,488 generalized to nalorphine whereas the dextroisomers did not. Generalization to nalorphine did not occur with the mu opiate agonists, morphine, methadone and meperidine, or the nonopiate compounds, phencyclidine, ketamine and chlorpromazine. The results suggest that a kappa opiate receptor mechanism mediates the discriminative effects of nalorphine in the rhesus monkey, which may also be involved with the naloxone-sensitive, sedative and dysphoric effects of nalorphine in humans.

Topics: Animals; Benzodiazepines; Benzomorphans; Conditioning, Operant; Cyclazocine; Discrimination Learning; Dose-Response Relationship, Drug; Ethylketocyclazocine; Macaca mulatta; Male; Nalorphine; Naloxone; Phenazocine; Receptors, Opioid; Receptors, Opioid, kappa