mr-2266 and quadazocine

Effects of naltrexone and of other drugs in decreasing rates of schedule-controlled responding were studied in squirrel monkeys treated weekly with naltrexone while responding under fixed-ratio schedules of either food presentation (FP) or stimulus-shock termination (SST). By the 5th week of treatment, sensitivity to the rate-decreasing effects of naltrexone had increased 32-fold in FP monkeys (supersensitivity) but had not changed in SST monkeys; continued weekly injections of naltrexone did not change the effects of naltrexone further in either group. FP monkeys were more sensitive than SST monkeys to the rate-decreasing effects of other opioid antagonists and mixed agonist-antagonists; however, for some compounds (e.g., MR 2266) differences between groups did not exceed differences reported in nonsensitized monkeys responding under similar schedule conditions. Differences in sensitivity between FP and SST monkeys appeared to be stereospecific; FP monkeys were 28 times more sensitive than SST monkeys to (-)-cyclazocine, but equally sensitive to (+)-cyclazocine. Sensitivity to opioid agonists and to some nonopioids varied by less than 3-fold between groups and doses of lithium that decreased responding in FP monkeys had no effect in SST monkeys. Neither acute nor repeated injections of morphine altered the sensitivity of FP or SST monkeys to naltrexone; however, morphine attenuated the rate-decreasing effects of naltrexone in FP monkeys, and naltrexone reversed the rate-decreasing effects of morphine in all monkeys. Super-sensitivity to opioid antagonists in squirrel monkeys is behaviorally and pharmacologically selective as well as stereospecific. Although other effects of antagonists might contribute to supersensitivity, opioid antagonistic action appears to be one important component of supersensitivity and cross-supersensitivity among opioid antagonists.

Topics: Animals; Azocines; Behavior, Animal; Benzomorphans; Diprenorphine; Drug Administration Schedule; Morphine; Naloxone; Naltrexone; Receptors, Opioid; Saimiri

A number of opioid antagonists (TENA, naloxone, Mr 2266, WIN 44441) were evaluated for their selectivity in antagonizing the effect of mu, kappa, and delta agonists in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Among these four antagonists, TENA was the most potent and the only ligand which was selective for kappa receptors. In this regard TENA was approximately 27-times more effective in antagonizing the kappa agonist, U-50488H, relative to the mu agonist, morphine, and it was about 5-times more effective against ethylketazocine (EK) relative to morphine. At the same concentration (20 nM) TENA did not significantly antagonize the delta agonist, [D-Ala2,D-Ala5]enkephalin (DADLE), in the MVD. Also, TENA was more effective than naloxone, EK, or U-50488H in protecting kappa receptors from irreversible blockage by beta-CNA. The results of this study indicate that TENA is the most selective kappa antagonist yet reported.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Azocines; Benzomorphans; Cyclazocine; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Ethylketocyclazocine; Guinea Pigs; Ileum; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vas Deferens

Male and female rats of the three Roman strains (Roman High-, Roman Low-, and Roman Control Avoidance; RHA, RLA and RCA, respectively) were familiarized with a highly palatable sweetened milk in a daily 30 min test. The animals were never food- or water-deprived prior to the test. Daily milk intake stabilised at a high level before drug tests were initiated. Effects of naloxone, diprenorphine, WIN 44,441-3, MR2266, MR2267, and ICI 154129 on milk consumption were investigated. Naloxone, diprenorphine and MR2266 each had comparable anorectic effects across strains and sexes. WIN 44,441-3 was relatively ineffective; MR2267 and ICI 154129 were without effect on milk consumption.

Topics: Animals; Appetite Depressants; Azocines; Benzomorphans; Diprenorphine; Enkephalin, Leucine; Feeding Behavior; Female; Male; Naloxone; Narcotic Antagonists; Rats; Receptors, Opioid; Sex Factors; Species Specificity

Pigeons trained to peck a key on a fixed-ratio 20 schedule of food presentation were used to evaluate the antagonistic and rate-suppressing effects of several opioid antagonists. Antagonism was measured as an increase in the dose of morphine necessary to suppress responding. Antagonist pretreatments increased the suppressing dose of morphine, although the magnitude of the increase varied markedly among different antagonists. Rank order of the maximum increase in the suppressing dose of morphine that each antagonist produced was: naltrexone = WIN 44,441 greater than beta-funaltrexamine greater than naloxone = buprenorphine greater than MR 2266 greater than diprenorphine. The time course of morphine antagonism also differed among antagonists. For example, buprenorphine was not an effective antagonist when administered 10 min before morphine, but was effective when administered either 2 or 12 hr before morphine. beta-Funaltrexamine and WIN 44,441 had the longest durations of antagonist action; each antagonized the rate-suppressing effects of morphine from 10 min to 24 hr. The effective antagonistic dose range (i.e., doses which blocked the rate-suppressing effects of morphine without affecting response rate when administered alone) and maximum increase in the suppressing dose of morphine were highly correlated, suggesting that the direct effects of most of these antagonists on responding may limit their effectiveness as morphine antagonists.

Topics: Animals; Azocines; Benzomorphans; Buprenorphine; Columbidae; Conditioning, Operant; Diprenorphine; Dose-Response Relationship, Drug; Morphine; Naloxone; Naltrexone; Narcotic Antagonists

In prehydrated rats, the administration of kappa-opiate agonists such as bremazocine, ethylketocyclazocine or compound Upjohn-50,488 produced a dose-dependent increase in urine output and decreased the concentration of Na+ and K+ in the urine as compared to that of saline-treated rats. The diuretic effect of bremazocine lasted at least 3 h. The increase in urine output was independent of the hydration state of the rat since in non water-loaded animals, bremazocine produced proportionally as much diuresis and a decrease in the output of urine electrolytes of about the same magnitude as that observed in the prehydrated animals treated with the opioid. In contrast to the diuretic action of kappa-opiate agonists, the administration of antagonists with high affinity for the kappa-opiate receptor (Win 44,441 or Mr 2266) decreased dose dependently the output of urine and reduced very significantly the total output of Na+ and K+. Whereas 2 mg/kg naloxone did not block the bremazocine-induced urinary effects, 1 mg/kg Win 44,441 or Mr 2266 antagonized competitively the renal activity of bremazocine. The results are interpreted to suggest that the kappa-opiate receptor may be involved in the regulation of fluid and electrolyte balance.

Topics: Animals; Azocines; Benzomorphans; Cyclazocine; Diuresis; Ethylketocyclazocine; Female; Injections, Intraperitoneal; Morphinans; Morphine; Naloxone; Potassium; Rats; Rats, Inbred Strains; Receptors, Opioid; Sodium; Water-Electrolyte Balance

Diprenorphine, naloxone, MR-2266-BS and WIN-44,441-3 were compared for their ability to antagonize morphine analgesia and to decrease deprivation-induced drinking in rats. Diprenorphine and naloxone were markedly more potent (32x) than MR-2266-BS and WIN-44,441-3 in antagonizing the analgesic effects of morphine. In contrast, diprenorphine, naloxone and MR-2266-BS decreased deprivation-induced drinking over a similar dose range. The doses required to reduce fluid consumption were higher than those necessary to antagonize morphine. WIN-44,441-3 was ineffective in decreasing drinking. The relatively similar potencies of diprenorphine, naloxone and MR-2266-BS for decreasing deprivation-induced drinking suggest that the effect on drinking involves antagonist activity at a kappa-opioid receptor.

Topics: Animals; Azocines; Benzomorphans; Drinking; Male; Naloxone; Narcotic Antagonists; Rats; Receptors, Opioid

To test the hypothesis that dynorphin is a K-opiate agonist acting on the myenteric plexus, the potency of two benzomorphan antagonists (Win 44, 441 and Mr 2266) to block the inhibitory action of dynorphin, enkephalins and opioid alkaloids was determined on the longitudinal muscle preparation of the guinea pig ileum. The effectiveness of these antagonists was compared to that of naloxone. Antagonistic potency was established by calculating the apparent antagonist dissociation constant, Ke, as derived from Schild plots. Win 44, 441 and Mr 2266 were about 7-8 times more potent than naloxone against dynorphin, dynorphin-(1-13) or ethylketocyclazocine. Although the Ke obtained with Win 44, 441 or Mr 2266 against dynorphin or ethylketocyclazocine were significantly lower than those of naloxone, the values obtained for these antagonists did not differ significantly in the case of each of these agonists. With respect to the antagonism of the enkephalins or normorphine, Win 44, 441 was the most potent antagonist. Its Ke value for the enkephalins was 2.5-3 times lower than those for dynorphin or ethylketocyclazocine and in comparison to naloxone, Win 44, 441 was about 5 times more potent. Although Mr 2266 was a potent antagonist of dynorphin, ethylketocyclazocine, the enkephalins or normorphine, it showed no selectivity of action. The fact that the 3 opiate antagonists evidenced similar Ke values for dynorphin and ethylketocyclazocine, but different ones for the enkephalins or normorphine supports the conclusion that dynorphin activates preferentially K- but not mu-opiate receptors in the myenteric plexus.

Topics: Animals; Azocines; Benzomorphans; Cyclazocine; Dynorphins; Endorphins; Enkephalins; Ethylketocyclazocine; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphine Derivatives; Muscle, Smooth; Naloxone; Narcotic Antagonists