mr-2266 and tifluadom

Dynorphin 1-17 has been suggested to be the endogenous ligand for kappa opioid receptors. In this study motor effects of dynorphin 1-17, its N-terminal fragments d-Pen2,d-Pen5-enkephalin (DPDPE) and d-Ser2-[Leu5]enkephalin-Thr (DSLET) without or with pretreatment with naloxone, (-)-2-(furylmethyl)-noretacocine (Mr 2266) or tetrodotoxin (TTX) on the isolated rat colon were compared with those of nonpeptide kappa opioid receptor agonists. Intraluminal pressure changes were measured by perfusion manometry in preparations maintained in a standard organ bath. Dynorphin 1-17, 1-9, 1-8, 1-6, [Leu5]enkephalin, DPDPE and DSLET dose dependently stimulated the tone in the proximal, middle and distal colon with the maximum response at 10(-6) to 10(-5) M. The stimulation produced by Tyr-Gly-Gly-Phe and Tyr-Gly-Gly was 60 and 600 times less potent, respectively. Concentrations of 10(-10) to 10(-6) M des-Tyr1-[Leu5]enkephalin, dynorphin 3-13, 6-17, 1-methyl-2-(3-thienylcarbonyl)-amino-ethyl-5-(2-fluorophenyl)-H-2,3 dihydro-1,4-benzodiazepine, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl) cyclohexyl)-benzene- acetamide-methane sulfonate and (5a,7a,8B)-(-)-N-methyl-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)-dec-8- yl) benzeneacet-amide produced no changes in motor activity of the rat colon. Only doses exceeding 10(-6) M of the latter three substances stimulated colonic tone. This action was inhibited neither by naloxone nor by Mr 2266. In contrast, the stimulation by dynorphin 1-17 and 1-6 was inhibited to a greater extent by naloxone than by Mr 2266.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antihypertensive Agents; Benzeneacetamides; Benzodiazepines; Benzomorphans; Colon; Diuretics; Dynorphins; Gastrointestinal Motility; In Vitro Techniques; Male; Muscle, Smooth; Naloxone; Narcotic Antagonists; Pressure; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Pigeons were trained to discriminate a dose of either 0.01 mg/kg of bremazocine or 0.05 mg/kg of fentanyl from water using a two-key drug discrimination procedure. During tests of substitution, the selective kappa-opioid agonists bremazocine, U50, 488 and tifluadom substituted for the bremazocine stimulus, whereas the less selective kappa-opioid agonists ethylketocyclazocine, levallorphan, proxorphan and nalorphine substituted for the fentanyl stimulus. The full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol, as well as the partial agonists nalbuphine, butorphanol and buprenorphine, substituted for the fentanyl stimulus. Compounds with partial-opioid agonist effects, namely nalbuphine, butorphanol, buprenorphine, proxorphan, levallorphan and nalorphine, produced 50% fentanyl-appropriate responding at doses 25 to 369.2 times smaller than the doses required to decrease response rates to 50% of control values. In contrast, the full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol produced 50% fentanyl-appropriate responding at doses only 1.3 to 10.9 times smaller than those required to decrease response rates by 50%. During tests of antagonism, both naloxone and Mr2266 produced a dose-dependent attenuation of the stimulus effects of bremazocine and fentanyl, whereas beta-funaltrexamine antagonized the stimulus effects of fentanyl but not bremazocine. Although bremazocine has been reported to have mu-opioid antagonist effects, it failed to antagonize the stimulus effects of the training dose of fentanyl. The present investigation establishes further that pigeons can discriminate selective kappa-opioid agonists from mu-opioid agonists and that in pigeons the classification of numerous opioid compounds on the basis of their kappa-like or mu-like stimulus effects differ from those in rat and monkey. In addition, under the drug discrimination procedure the actions of compounds classified as partial-opioid agonists can be differentiated from those of full mu-opioid agonists on the basis of the ratio of the dose required to engender fentanyl-like stimulus effects to the dose required to reduce response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Columbidae; Cyclazocine; Discrimination Learning; Ethylketocyclazocine; Fentanyl; Morphinans; Naloxone; Narcotics; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effects of mu-agonists (morphine, fentanyl) and kappa-agonists (U-50,488, U-69,593, bremazocine, nalbuphine, tifluadom) on the electroconvulsive threshold were studied in mice. The threshold could be significantly elevated by all drugs tested in a dose range that was in the order of magnitude of the antinociceptive ED50. Mice tolerant to the antielectroshock effect of morphine still reacted to U-69,593. The antagonism of the anticonvulsant effect by the mu-antagonist naloxone and the kappa-antagonist MR 2266 was receptor-specific only with fentanyl and U-50,488. The other opioid agonists were either antagonized by both drugs (morphine, U-69,593, bremazocine, nalbuphine) or even by the opposite antagonist (tifluadom). A synergistic effect of mu- and kappa-stimulation is assumed for the mediation of the antielectroshock effect of opioid drugs, but drugs with high affinity and intrinsic activity at one receptor type (fentanyl, U-50,488) are obviously able to bring about their antielectroshock effect through the one respective opioid binding site.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzeneacetamides; Benzodiazepines; Benzomorphans; Electroshock; Fentanyl; Male; Mice; Morphinans; Morphine; Nalbuphine; Naloxone; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Seizures

The effects of oral administration of selective mu (D-Ala2, N-Me-p-nitro-Phe4, Gly5-ol-DAGO, morphine) and/or kappa (3,4 dichloro-N-methyl N [2-(1. fyrrolidinyl) cyclohexyl]-benzene acetamide-U-50488, tifluadom) or mixed agonist (N-desmethyltrimebutine) opioid on gastric emptying have been evaluated using a radiolabelled [57Co] canned food meal in dogs fitted with gastric cannulas. In control conditions (placebo) the percentage of solids emptied 1 h after feeding was 27.3 +/- 4.1%. When given orally at doses of 0.01 to 0.5 mg kg-1, U-50488 increased significantly (P less than 0.05) by 29.1 to 60.8% in a dose-related manner (r-0.94, P less than 0.01) the amount of gastric emptying of the meal in 1 h. This effect was reproduced by oral administration of tifluadom (0.01 to 0.1 mg kg-1) and by N-desmethyltrimebutine (0.1 to 1 mg kg-1). In contrast, the gastric emptying was unaffected by DAGO and morphine at low doses (0.01 and 0.1 mg kg-1) but significantly (P less than 0.05) slowed with higher doses of morphine. The increases in amount of gastric emptying induced by tifluadom, U-50488 and N-desmethyltrimebutine were abolished by previous administration of naloxone (0.1 mg kg-1 i.v.) and [(3-furylmethyl) noretazocine]-MR 22-66 (0.1 mg kg-1 i.v.). These results indicate that orally administered kappa, but not mu agonists at doses not exceeding 1 mg kg-1 enhance the amount of gastric emptying of a solid meal in dogs and suggest that this is due to a selective local stimulation of kappa mucosal or submucosal opiate receptors at antroduodenal level.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animal Feed; Animals; Benzodiazepines; Benzomorphans; Diuretics; Dogs; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Female; Gastric Emptying; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The influence of oral (p.o.) administration of kappa-(U-50488, tifluadom) and mu- (morphine, DAGO) opioid substances on gastric emptying of liquids and solids in a standard canned dog food meal was evaluated using a double-radiolabeled technique in dogs fitted with gastric cannulas. One hour after feeding, 28.6% +/- 3.6% (mean +/- SD) of the solid phase and 27.1% +/- 8.6% of the liquid phase of the meal had been emptied. Both U-50488 and tifluadom given orally (0.01-0.1 mg/kg) significantly increased (p less than 0.05) the 1-h emptying of the solid phase of the meal by 23.1%-49.6%. In contrast, both drugs significantly reduced emptying of liquids. These effects were not reproduced when similar doses were given intravenously. Oral administration of morphine or DAGO (0.01-0.1 mg/kg) did not affect gastric emptying, whereas an inhibited emptying of solids was observed for morphine at a higher dose (1 mg/kg p.o.). At a dose of 100 micrograms/kg i.v. both naloxone and MR 2266 (0.1 mg/kg) abolished the effects of orally administered U-50488 on gastric emptying of solids and liquids. It is concluded that kappa- but not mu-agonists act locally to alter gastric emptying of a standard meal in dogs, having opposite effects on solid and liquid phases. A selective local stimulation of kappa mucosal or submucosal receptors of the gastroduodenal area may explain such effects.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Administration, Oral; Animal Feed; Animals; Benzodiazepines; Benzomorphans; Dogs; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Female; Gastric Emptying; Injections, Intravenous; Morphinans; Morphine; Naloxone; Pyrrolidines

Tifluadom, a benzodiazepine with purported opioid receptor-related analgesic properties, was studied in regard to its acute effects on power spectra of the EEG to demonstrate vigilance changes. Additionally, somatosensory-evoked potentials (SEP) were derived to evaluate its effect on the propagation of impulses in sensory nerve fibers. In order to demonstrate stereospecificity, the two enantiomers of tifluadom (KC-5911 and KC-6128) were given in graded doses (20, 40, 80, 160 micrograms/kg i.v.) to awake, unrestrained and trained dogs at 10-min intervals. KC-6128, but not its optical counterpart KC-5911, induced synchronization of the EEG at 20 micrograms/kg with an increase of power (pW) in the delta (1-4 Hz; +300%), theta (4-8 Hz; +450%), and alpha (8-13 Hz +90%) bands. This was accompanied by a reduction of power in the fast beta domain (13-30 Hz; -95%). Vigilance changes were reflected in the beta/delta quotient which dropped from 3.7 (control) to 0.8 (20 micrograms/kg) and to 0.3 (40 micrograms/kg). A further increase in the dose resulted in saturation. At the highest dose (160 micrograms/kg) there was an additional reduction of the beta/delta quotient to 0.1. In order to unmask the receptor population, possibly mediating the observed changes, a benzodiazepine antagonist and opioid antagonists were given. Ro 15-1788 (240 micrograms/kg) had no effect and naloxone (20 micrograms/kg) induced a short term (5 min) arousal. Only the kappa antagonist Mr 2266 (20 micrograms/kg) induced a reversal of the beta/delta quotient back to 5.5. KC-5911 induced an insignificant drop in the beta/delta quotient which was reversed by Ro 15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzodiazepines; Benzomorphans; Dogs; Electroencephalography; Evoked Potentials; Flumazenil; Naloxone; Receptors, Opioid; Receptors, Opioid, kappa; Stereoisomerism

A derivative of the 1,4-benzodiazepine series with reported opioid activity was evaluated in regard to its effect on central nervous activity in the awake canine. Additionally a possible benzodiazepine- or opioid-receptor interaction was evaluated by using specific antagonists. In 10 experiments increasing doses of tifluadom (5, 10, 20, 40, 80 micrograms/kg) modified somato-sensory-evoked potentials (SEP) inducing a dose-related latency change (40-80 micrograms/kg) and a suppression (80 micrograms/kg) of the P50-peak. Both effects are interpreted as a modification of stimuli reaching the somatosensory cortex. EEG-spectral analysis was characterized by a dose-related decrease of power in the higher frequency range (13-40 Hz) accompanied by an increase of power in the lower band (0.5-3.5 Hz). This effect was paralleled by deep sedation. The specific benzodiazepine antagonist Ro 15-1788 (240 micrograms/kg) was ineffective in reversing central nervous EEG- and SEP-changes. Naloxone (20 micrograms/kg) induced a short-term (5 min) arousal and a partial reversal of SEP-changes. The specific opioid-kappa-antagonist Mr 2266 (20 micrograms/kg) however, induced a long lasting return of power spectra and SEP-changes back to control. This results suggest that tifluadom, although being structurally a benzodiazepine, interacts with an opioid sub-receptor of the kappa-type, which is known to induce sedation and supraspinal analgesia without respiratory depression.

Topics: Animals; Benzodiazepines; Benzodiazepinones; Benzomorphans; Brain; Dogs; Dose-Response Relationship, Drug; Electroencephalography; Evoked Potentials, Somatosensory; Flumazenil; Naloxone

There is now considerable evidence that opioid agonists and benzodiazepines increase food and water intake in a variety of animal species. The appetitive effects of the novel opioid-benzodiazepine tifluadom have been investigated. (+/-)-Tifluadom significantly increased food intake in freely-feeding rats. This stimulation of appetite was attributable principally to the activity of the (+)-isomer. Furthermore tifluadom-induced feeding was blocked by the opioid antagonists naloxone, naltrexone, Mr 1452 and Mr 2266 but not by the delta-opioid receptor antagonist ICI 154, 129, or by the benzodiazepine antagonist Ro 15-1788. These results suggest that tifluadom exerts its effect on food intake by interaction with opioid as opposed to benzodiazepine receptors and that this activity is mediated by kappa and/or mu- rather than delta-opioid receptor sub-types.

Topics: Animals; Benzodiazepines; Benzodiazepinones; Benzomorphans; Convulsants; Eating; Enkephalin, Leucine; Flumazenil; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Stereoisomerism