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PubMed1986

Characterization of opioid receptors modulating noradrenaline release in the hippocampus of the rabbit.

Noradrenaline (NA) release and its modulation via presynaptic opioid receptors were studied in rabbit hippocampal slices, which were preincubated with [3H]NA, continuously superfused in the presence of 30 microM cocaine and stimulated electrically. The evoked release of [3H]NA was strongly reduced by the preferential kappa-agonists ethylketocyclazocine, dynorphin A1-13, dynorphin A, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] -benzeneacetamide (U-50,488), and (-)-5,9-dimethyl-2'-OH-2-tetrahydrofurfuryl-6,7-benzomorphan [(-)-MR 2034], whereas (+)-MR 2035 [the (+)-enantiomer of (-)-MR 2034] was ineffective. In contrast, the preferential delta-agonists Leu-enkephalin, Met-enkephalin, and D-Ala2-D-Leu5-enkephalin (DADLE) as well as the mu-agonists morphine, normorphine, D-Ala2-Gly-ol5-enkephalin (DAGO), and beta-casomorphin 1-4 amide (morphiceptin) were much less potent. However, in similar experiments on rat hippocampal slices DAGO (1 microM) was much more potent than ethylketocyclazocine (1 microM) or DADLE (1 microM). (-)-N-(3-furylmethyl)-alpha-noretazocine [(-)-MR 2266], 1 microM, a preferential kappa-antagonist, antagonized the effect of ethylketocyclazocine more potently than (-)-naloxone or (+)-MR 2267 [the (+)-enantiomer of (-)-MR 2266]. Given alone, (-)-MR 2266 slightly and (+)-MR 2267 (1 microM each) greatly enhanced NA release, apparently due to alpha 2-adrenoceptor blockade since their effects were completely abolished in the presence of yohimbine (0.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Pharmacological profile of various kappa-agonists at kappa-, mu- and delta-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain.

1. The potency, relative efficacy and selectivity of a series of kappa-opioid receptor agonists at the mu-, delta- and kappa-opioid receptors mediating inhibition of electrically-induced (radiolabelled) neurotransmitter release from superfused rat brain slices was determined. 2. With regard to their potencies at kappa-receptors mediating inhibition of striatal [3H]-dopamine release, the highest pD2 value (8.7) was found for bremazocine and the lowest (7.1) for U50488; the pD2 values for ethylketocyclazocine (EKC), tifluadom, U69593 and PD117302 were between 8.0 and 8.3. There were no marked differences between the relative efficacies of the kappa-agonists (maximum inhibition being 60-70%). In contrast to the other kappa-agonists, at a concentration of 1 microM, PD117302 caused a significant (25-40%) increase of the spontaneous efflux of tritium. 3. None of the kappa-agonists significantly affected striatal [14C]-acetylcholine (ACh) release, with the exception of a slight inhibitory effect of EKC. The delta-receptor-mediated inhibitory effect of [D-Ala2, D-Leu5]enkephalin (DADLE) on [14C]-ACh release was antagonized in a concentration-dependent manner by bremazocine (0.1 and 1.0 microM) and also partially by EKC (1 microM), but not by the other kappa-agonists. The pA2 value for bremazocine as an antagonist at the delta-receptors involved was 8.0, compared to 7.6 for naloxone. 4. None of the kappa-agonists significantly affected cortical [3H]-noradrenaline (NA) release, with the notable exception of tifluadom, which strongly inhibited release by activating mu-receptors. The mu-receptor-mediated inhibitory effect of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) on [3H]-NA release was antagonized in a concentration-dependent manner by bremazocine and EKC, but not by the other K-agonists. The pA2 value for bremazocine as an antagonist at the mu-receptors involved was 8.2, compared to 8.6 for naloxone. 5. Thus, whereas U69593 and PD1 17302 display high potency and selectivity towards K-opioid receptors, the potent benzomorphan K-agonists bremazocine and EKC also appear to be strong mu-opioid receptor antagonists.

Acetylcholine↗
PubMed1996

The site of anti-arthritic action of the kappa-opioid, U-50, 488H, in adjuvant arthritis: importance of local administration.

1. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (kappa)-opioid, U-50,488H (trans-(+/-)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]- benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, kappa-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a kappa-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the anti-arthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (+/-)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (+/-)-U-50,488H on radiology and histology varied according to treatment time. Administration of (+/-)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (+/-)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (+/-)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 +/- 1.6 vs 19.5 +/- 0.8 mg kg-1). 3. Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (+/-) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+/-)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4. Both the peripherally selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), were able to reverse fully the peripheral anti-arthritic effects of U-50,488H, indicating that it exerts its effects through peripheral kappa-opioid receptors. 5. Taken together, these results not only confirm our previous findings that demonstrate anti-arthritic effects of U-50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral kappa-receptors in the arthritic joint. Peripherally acting kappa-opioid agonists should lead to new therapies for arthritis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2005

Bremazocine: a kappa-opioid agonist with potent analgesic and other pharmacologic properties.

Bremazocine is a kappa-opioid receptor agonist with potent analgesic and diuretic activities. As an analgesic it is three- to four-times more potent than morphine, as determined in both hot plate and tail flick tests. Bremazocine and other benzomorphan analogs were synthesized in an effort to produce opiates with greater kappa-opioid receptor selectivity and with minimal morphine-like side effects. Unlike morphine bremazocine is devoid of physical and psychological dependence liability in animal models and produces little or no respiratory depression. While bremazocine does not produce the characteristic euphoria associated with morphine and its abuse, it has been shown to induce dysphoria, a property that limits its clinical usefulness. Similarly to morphine, repeated administration of bremazocine leads to tolerance to its analgesic effect. It has been demonstrated that the marked diuretic effect of bremazocine is mediated primarily by the central nervous system. Because of its psychotomimetic side effects (disturbance in the perception of space and time, abnormal visual experience, disturbance in body image perception, de-personalization, de-realization and loss of self control) bremazocine has limited potential as a clinical analgesic. However, its possible utility for the therapy of alcohol and drug addiction warrants further consideration because of its ability to decrease ethanol and cocaine self-administration in non-human primates. In addition, the ability of bremazocine-like drugs to lower intraocular pressure and to minimize ischemic damage in animal models suggests their possible use in the therapy of glaucoma and cardiovascular disease.

Analgesics↗
PubMed1982

Stereospecific inhibition of oxotremorine-induced antinociception by (+)-isomers of opioid antagonists: comparison with opioid receptor agonists.

The antagonistic effects of the two benzomorphan opioid antagonists, Mr-1452 and Mr-2266 and their respective (+)-isomers Mr-1453 and Mr-2267 upon morphine, ethylketocyclazocine (EKC), D-ala2-D-leu5-enkephalinamide (BW 180-C) and oxotremorine (OTMN) antinociceptive activity in mice were investigated. Pretreatment with either Mr-1452 (2.0 mg Kg-1 i.p.) or Mr-2266 (2.0 mg kg-1 i.p.) significantly antagonized the antinociceptive effects of the three opioid agonists in the hot plate test, but were ineffective against OTMN, which in contrast was antagonized by the (+)-isomers. Interaction between the antagonists and submaximal analgesic doses of the opioids or OTMN produced similar results in the tail immersion assay. However, the effect of Mr-2267 on OTMN was biphasic and this contrasted with Mr-1453 which produced consistent and graded antagonism.

Animals↗
PubMed1988

Stereoselectivity of kappa-opiate receptor ligands in inhibiting the binding of [3H][3-MeHis2]thyrotrophin releasing hormone to brain membranes.

The effect of (+/-)-, (-)- and (+)-isomers of several ligands for kappa-opiate receptors on the binding of [3H][3-MeHis2]-thyrotrophin releasing hormone ([3H]MeTRH) to rat brain membranes has been determined. [3H]MeTRH bound to rat brain membranes at a single high affinity site with maximal binding capacity (Bmax) of 48 +/- 2 fmol(mg protein)-1, and an apparent dissociation constant, Kd of 4.6 +/- 0.2 nM. At a concentration of 2 nM, the specific binding of [3H]MeTRH was 12.3 +/- 0.6 fmol(mg protein)-1. The isomers of ketocyclazocine, tifluadom (1-methyl-2-(3-thienylcarbonyl) aminomethyl-5-(2-fluorophenyl) H-2,3-dihydro-1,4-benzodiazepine), and alpha-5,9-diethyl-2'-hydroxy-2-(3-furylmethyl)-6,7-benzomorphan [MR 2266 (-), MR 2267 (+)] were used for interaction studies. The (-)-isomer of each of the above drugs was more potent than the (+)-form in inhibiting the binding of [3H]MeTRH to brain membranes, whereas the (+/-)-forms had activity intermediate between (-)- and (+)-forms. The order of activity of kappa-ligands was tifluadom greater than MR 2266 greater than ketocyclazocine. It is concluded that kappa-opiate drugs inhibit the binding of [3H]MeTRH to brain membranes in a stereoselective manner with tifluadom being the most potent drug.

Animals↗
PubMed1986

Psychotomimesis mediated by kappa opiate receptors.

The kappa opioid agonists are analgesics that seem to be free of undesired morphine-like effects. Their dysphoric actions observed with the kappa agonist cyclazocine are thought to be mediated by an action at sigma-phencyclidine receptors. The benzomorphan kappa agonist MR 2033 is inactive at sigma-phencyclidine receptors. In male subjects, the opiate-active (-)-isomer, but not the (+)-isomer, elicited dose-dependent dysphoric and psychotomimetic effects that were antagonized by naloxone. Thus, kappa opiate receptors seem to mediate psychotomimetic effects. In view of the euphorigenic properties of mu agonists, our results imply the existence of opposed opioid systems affecting emotional and perceptual experiences.

Adult↗
PubMed1989

Pharmacological characterization of the binding of [3H]bremazocine in guinea-pig brain: evidence for multiplicity of the kappa-opioid receptors.

In guinea-pig brain, [3H]bremazocine has a binding capacity of 27.2 pmol/g wet tissue, which is statistically different from that of [3H]ethylketazocine (14.7 pmol/g wet tissue) or the sum of the individual binding capacities of mu-, delta-, and kappa-selective ligands (15.0 pmol/g wet tissue). Saturation studies of [3H]bremazocine performed in the presence of unlabelled mu-, delta-, and kappa-blockers still reveal a homogeneous population of binding sites. [3H]Bremazocine under suppressed conditions displays at these sites a Kd of 2.51 nM with a binding capacity of 9.15 pmol/g wet tissue. We have performed the pharmacological characterization of these additional opioid binding sites. Displacement curves measured with a number of opioid substances were all best fitted to a one-site model. The stereoselectivity of these additional sites was demonstrated by using two groups of stereoisomers. Oripavine and benzomorphan opioids were among the most potent drugs at the [3H]bremazocine sites (mu + delta + kappa suppressed). Diprenorphine, bremazocine, cyclazocine, and ethylketazocine displayed apparent affinities constants (1/Ka) of 8.66, 7.57, 21.4, and 38.0 nM, respectively at those sites. The kappa-selective drugs U50488, U69593, PD117302, and tifluadom were inhibitors of the binding of [3H]bremazocine at these sites with apparent affinities of 113, 268, 76.9, and 47.9 nM. All mu- or delta-selective drugs tested in this study have caused weak or no inhibition of the binding. Correlation analyses were done between the different affinities measured at the [3H]bremazocine sites (mu + delta + kappa suppressed) and those observed at the known mu-, delta-, and kappa-sites of the guinea-pig brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Central kappa- and mu-opiate receptors mediate ACTH-release in rats.

The control of ACTH secretion by opiates seems to involve stimulatory and inhibitory pathways, since opiate agonists and antagonists are capable of releasing ACTH in conscious rats. To elucidate the role of different opiate receptors in the control of ACTH release, rats were treated with receptor-selective opiate agonists and antagonists. The mu-opiate agonists, morphine and (D-Ala2, MePhe4, Gly5-ol)enkephalin, and the benzomorphan kappa-opiate agonists, MR 2034 and MRZ 2549, both stimulated ACTH release after central or peripheral injection. The effects of morphine, but not those of MR 2034, were blocked by a low dose of naloxone (50 micrograms/kg) and by the mu-receptor antagonist, beta-funaltrexamine. A 20 times higher dose of naloxone also blocked the effects of the kappa-agonist. Our data suggest that both mu- and kappa-opiate receptors are involved in the stimulation of ACTH release in rats.

Adrenocorticotropic Hormone↗
PubMed1991

On the actions of the growth hormone-releasing hexapeptide, GHRP.

GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2 or GHRP) releases GH by a unique and complementary dual site of action on the hypothalamus and pituitary. These effects are mediated via non-GH-releasing hormone (non-GHRH) and nonopiate receptors in rats. Select types of opiates are known to release GH by a hypothalamic site of action, and thus, the dermorphin heptapeptide and benzomorphan opiate agonist 2549 used in this study presumably act on the hypothalamus to release GH. Neither dermorphin nor 2549 released GH or augmented the GH responses of GHRP or GHRH in vitro by a direct pituitary action, while GHRH antiserum inhibited the GH response of both dermorphin and 2549 in vivo. Evidence indicates that these opiates and GHRP administered together synergistically release GH, demonstrating the independent action(s) of GHRP and the opiates. Present data indicate that one of the major differences in the actions of dermorphin, 2549, and GHRP is the inhibition of somatostatin (SRIF) release by the opiates but not by GHRP. Although the actions of dermorphin, 2549, and GHRP on GH release are GHRH dependent, release of endogenous GHRH does not explain how GH is released synergistically by the combination of these peptides. It is proposed that dermorphin/2549 synergistically release GH with GHRP or GHRH because these opiates inhibit SRIF release. Since the GHRP plus GHRH synergistic GH release was not explained by inhibition of SRIF or stimulation of GHRH, an alternative mechanism is proposed to explain how GHRP synergistically release GH in combination with GHRH. The complementary, rather dramatic synergistic interaction of GHRP, GHRH, and dermorphin or GHRP, GHRH, and 2549 in releasing GH again strongly supports the independent actions of these compounds.

Amino Acid Sequence↗
PubMed1986

Anterior pituitary hormone responses to a kappa-opioid agonist in man.

The present study was designed to investigate pituitary hormone responses to a kappa-opiate receptor agonist in man. Normal men were given the racemic benzomorphan kappa-agonist MR 2033 or its levorotatory isomer MR 2034 iv. Plasma levels of PRL and GH markedly increased after injection of 3.5 micrograms/kg MR 2033 or 1.9 or 3.8 micrograms/kg MR 2034. These effects of MR 2033 were blocked by the opiate antagonist naloxone (10 mg), thereby demonstrating their mediation by opiate receptors. The kappa-agonist did not change plasma levels of LH and FSH. The secretion of TSH was significantly suppressed by MR 2033 and MR 2034, but this action was not antagonized by pretreatment with naloxone. The suppression of plasma TSH was, however, stereospecific since the (+)-isomer, MR 2035, did not affect TSH secretion. These data indicate that kappa-opiate receptors are located on neuronal pathways regulating GH, TSH, and PRL secretion. The pattern of pituitary responses elicited by the kappa-agonist differs from that of mu-opioid agonists, indicating differential endocrine functions for the endogenous agonists.

Adult↗
PubMed1986

Agonist and antagonist actions of buprenorphine on three types of opioid receptor in isolated preparations.

Both agonist and antagonist actions of buprenorphine on isolated preparations were studied. The Ke (equilibrium dissociation constant) values of both naloxone and Mr 2266 [(-)-2-(3-furylmethyl)-5, 9-diethyl-2'-hydroxy-6,7-benzomorphan] against buprenorphine and the ratio of IC50 (concentration of the drug to produce 50% inhibition of the twitch) value of buprenorphine after to before exposure of mouse vas deferens to beta-FNA (beta-fumarate methyl ester derivatives of naltrexone), an irreversible mu antagonist, suggest that buprenorphine acts as both a mu and kappa agonist on mouse vas deferens. The agonist effect of buprenorphine at relatively high doses on guinea-pig ileum and mouse vas deferens and the negative agonist effect on both rat and rabbit vas deferens indicate that buprenorphine acts as a partial agonist on isolated preparations. The Ke values of buprenorphine show that buprenorphine has about equal antagonist effectiveness against a mu and kappa agonist with approximately five-fold lower effectiveness against a delta agonist. The possible mechanisms for the several characteristic actions of buprenorphine on guinea-pig ileum such as the slow onset of action, the increased magnitude of inhibition after washing the tissue, the negative elimination of the inhibition by either washing the tissue or the naloxone administration, and the negative elimination of the antagonist action by washing the tissue were discussed.

Animals↗
PubMed1984

Comparative in vitro/in vivo autoradiography using the opiate ligand 3H-(-)-bremazocine.

Autoradiograms of rat brain sections were compared obtained from animals receiving a tritiated drug through intravenous injection or from precut sections incubated in vitro. The benzomorphan analogue 3H-(-)-bremazocine was used as ligand and its distribution to all different opioid binding sites was followed. Although the general distribution of opioid binding sites visualized on 3H-LKB ultrofilms was independent of the methodological approach used, the maximal number of such sites (Bmax) was greater in brain sections incubated in vitro than after in vivo drug application. Since the number of binding sites is highly dependent on the particular incubation condition used, this finding has no further relevance.

Animals↗
PubMed1991

Involvement of epsilon and kappa opioid receptors in inhibition of the tail-flick response induced by bremazocine in the mouse.

Bremazocine, a benzomorphan, has been reported to have kappa, mu and epsilon opioid receptor binding activities. The present studies were then designed to determine what types of opioid receptors and neurotransmitters were involved in inhibiting the tail-flick response induced by bremazocine in male ICR mice. U50, 488H, a prototypic kappa agonist, was used for comparison. Bremazocine, at doses from 0.1 to 1 microgram given i.c.v., dose-dependently inhibited the tail-flick response. The paw-licking hot plate response, even at high doses of bremazocine, was not completely inhibited. The inhibition of the tail-flick response induced by bremazocine (1 microgram) given i.c.v. was blocked by i.c.v. coadministration of beta-endorphin-(1-27) (3 and 6 micrograms), an epsilon opioid receptor antagonist and norbinaltorphimine (4 micrograms), a kappa opioid receptor antagonist. On the other hand, the inhibition induced by i.c.v. U50,488H (40 micrograms) was blocked by i.c.v. norbinaltorphimine, but not beta-endorphin-(1-27). D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2 (CTOP; 0.5 microgram) and beta-funaltrexamine (beta-FNA; 2.5 micrograms), selective mu opioid receptor antagonists, and ICI 174,864 (10 micrograms), a delta-opioid receptor antagonist, which blocked the effects induced by DAMGO (16 ng) and DPDPE (20 micrograms), respectively, did not block inhibition of the tail-flick response induced by bremazocine (1 microgram) given i.c.v. The inhibition of the tail-flick response induced by i.t. administration of bremazocine (1 microgram) was blocked by i.t. coadministration of norbinaltorphimine but not CTOP, ICI 174,864, or beta-endorphin-(1-27).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1989

Effects of kappa opioids on schedule-controlled behavior of squirrel monkeys.

The behavioral effects of U50,488 [( trans]-3,4-dichloro-N-methyl-N[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), bremazocine, Mr2266 [(-)-5,9-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan] and morphine were compared in squirrel monkeys responding under multiple fixed-ratio fixed-interval (FR FI) schedules of food presentation or stimulus-shock termination. Doses of bremazocine (0.001-0.003 mg/kg), U50,488 (0.03-0.1 mg/kg) and Mr2266 (1.0-3.0 mg/kg) that markedly increased overall rates of FI responding maintained by stimulus-shock termination had little effect on or only decreased overall rates of FI responding maintained by food presentation. Each of the kappa opioids decreased FR responding maintained by either consequence. Morphine (0.03-1.7 mg/kg) only decreased responding under all conditions. Pretreatment with Mr2266 (0.1 mg/kg) produced a 10-fold or more rightward shift in the dose-effect functions for morphine under the two multiple schedules and U50,488 under the multiple schedule of food presentation. A 3-fold higher dose of Mr2266 produced an approximately 10-fold rightward shift in the descending portion of the dose-effect functions for U50,488 and bremazocine under the schedule of stimulus-shock termination but did not appreciably alter their rate-increasing effects. Naltrexone (0.1 mg/kg) antagonized the effects of selected doses of morphine or bremazocine on overall rates of responding under the schedule of stimulus-shock termination. In contrast to its effects in combination with morphine, however, naltrexone (0.1-3.0 mg/kg) did not block alterations in patterns of FI responding produced by bremazocine.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Photoaffinity labeling of opiate receptors using intrinsically photoactive 3H-opiates.

Opiate receptors in rat and cow brain membranes have been labeled irreversibly using the intrinsic photolability of 3H-opiates. Membranes were incubated with 3H-ligand and then irradiated with UV light of 254 nm. Nonspecific binding was determined in the presence of 10 microM unlabeled levallorphan. Irreversible binding was defined as binding which survived heat or acid denaturation of membranes. Specific incorporation of label into denatured samples was observed only when unbound or loosely bound 3H-ligand was washed free from the membranes prior to irradiation. There was a general correlation between photosensitivity of the 3H-ligand and its ability to photolabel receptors. Hence, photolabeling presumably results by covalent attachment of highly reactive species generated during photochemical decomposition of ligand. With 3H-etorphine, optimal irradiation time was 5 min. In addition to 3H-etorphine, receptors could be labeled irreversibly with 3H-oxymorphone, 3H-dihydromorphine, and 3H-ethylketocyclazocine. Of the specific binding present in irradiated, nondenatured samples, 45-60% remained attached to receptors upon denaturation. 3H-Ethylketocyclazocine exhibited an 86% yield of incorporation. Signal-to-noise levels of 50-80% could be achieved in denatured samples. Therefore, this method provides a means of covalently labeling opiate receptors in high yield and with high signal-to-noise ratios. The opioid peptides, 3-H-D-Ala2,D-Leu5-enkephalin, 3H-D-Ser2,Leu5,Thr6-enkephalin, 3H-D-Ala2,Met5-enkephalin amide, and 3H-D-Ala2,N-MePhe4,Gly-ol5-enkephalin, as well as the benzomorphan, 3H-bremazocine, apparently lack the structural characteristics which allow photolabeling. 3H-Etorphine was incorporated at high specific activity into a glycoprotein fraction of bovine brain membranes which was retained on wheat germ agglutinin affinity columns. Unretained proteins were essentially unlabeled. 3H-Etorphine was also incorporated at high specific activity into proteins of 17,000 and less than 13,700 Da and, at lower specific activity, into a protein of 2.4 X 10(6) Da in guinea pig brain membranes when kappa receptors were selectively labeled. This method therefore allows labeling of specific membrane proteins and will prove useful in molecular characterization of opiate receptors.

Affinity Labels↗
PubMed1985

Effects of bremazocine on locomotor activity in DBA/2 and C57BL/6 mice.

The effects of the benzomorphan analogue bremazocine on locomotor activity were studied in DBA/2 (DBA) and C57BL/6 (C57) mice. Three sets of experiments were carried out. In a first set, bremazocine depressed activity in both strains, but DBA mice were more sensitive to the effects of the drug. In a second set of experiments the effects of bremazocine were antagonized by a per se ineffective dose (0.5 mg/kg) of the selective kappa-opioid receptor antagonist MR 1452, showing that they were mediated through an interaction with this sub-population of opioid receptors. In a third set of experiments the effects of bremazocine were enhanced by the administration of a per se ineffective dose (0.025 mg/kg) of haloperidol, showing the involvement of dopaminergic mechanisms.

Analgesics↗
PubMed1977

[Pharmacologically active polymers. 9th communication: retard forms of morphine antagonists (author's transl)].

Acryloyl, methacryloyl, N-vinylcarbamoyl, and methacryloyl-glycyl derivatives of the morphine antagonist (--)-alpha-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane have been synthesized. The different unsaturated derivatives were copolymerized with appropriate comonomers to yield water-soluble polymers. Pharmacological tests in mice showed a 2--30 fold increase in duration of action in comparison to the free antagonist. The binding of the antagonist to the polymers resulted in a reduced acute toxicity.

Animals↗