Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Benzomorphans”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

931 records · Page 52Linked to original sources
PubMed1993

Discriminative stimulus effects of BW373U86: a nonpeptide ligand with selectivity for delta opioid receptors.

Several opioid agonists were evaluated in pigeons trained to discriminate i.m. injections of sterile water from either the mu agonist morphine (5.6 mg/kg), the kappa agonist bremazocine (0.032mg/kg) or (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (BW373U86; 0.56 mg/kg). Pigeons were trained to peak one of two keys on a fixed-ratio 20 schedule for food reinforcement. The pattern of substitution of mu, kappa and delta selective agonists in the three groups of birds suggested that the discriminative stimulus effects of morphine, bremazocine and BW373U86 were different; however, a component of the discriminative stimulus effects of BW373U86 appeared to be shared with morphine. Apparent pA2 values for naltrexone with morphine, bremazocine and BW373U86 were 7.6, 6.8 and 6.3, respectively. The apparent pA2 value for naltrindole with BW373U86 was 8.3. Naltrindole (10.0 mg/kg) produced a 3-fold shift to the right in the dose-effect curve for morphine but did not antagonize bremazocine. Although results from the substitutions experiments suggested that a component of the BW373U86 discriminative stimulus was mediated through mu opioid receptors, the fact that naltrindole was 1000-fold more potent and naltrexone was 30-fold less potent in antagonizing BW373U86 than morphine indicated that the discriminative effects of BW373U86 were also mediated through delta opioid receptors.

Amino Acid Sequence↗
PubMedDate not supplied

[The role of second messengers in the modulation of the plasticity of the cholinoreceptors of the snail RPa3 neuron by the opiate kappa agonist bremazocine].

In the paper was shown the participation of some second messengers in intracellular molecular mechanism of a decrease of RPa3 neuron cholinoreceptor plasticity by opiate kappa-agonist bremazocine during rhythmical acetylcholine application. This mechanism includes 1) inhibition of inositol-1,4,5-trisphosphate-dependent mobilization of deposited Ca2+ activating intracellular receptor calmodulin and 2) inhibition of the synthesis of the acyclic eicosanoids. It is possible to assume a specificity of this mechanism, so far as is not revealed the role of the second messengers under study in bremazocine inhibitors of RPa3 neuron somatic cholinoreceptors under the conditions of non-rhythmical acetylcholine application.

Acetylcholine↗
PubMed1993

Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys.

The effects of subcutaneously administered nor-binaltorphimine (nor-BNI; 1.0 and 3.2 mg/kg) were examined in the warm-water (50 degrees C and 55 degrees C) tail-withdrawal assay in rhesus monkeys (n = 3). Nor-BNI alone produced variable antinociceptive effects in 50 degrees C water up to 3.5 hr after administration but was completely ineffective against the 55 degrees C stimulus. Pretreatment with nor-BNI under conditions where it was devoid of antinociceptive effects produced rightward shifts in dose-effect curves for the kappa opioid agonist U50,488 for as long as 14 and 21 days after 1.0 and 3.2 mg/kg of nor-BNI, respectively. Under conditions when U50,488 dose-effect curves were shifted, nor-BNI (3.2 mg/kg) also caused rightward shifts in the antinociceptive dose-effect curves of the kappa agonist U69,593 but not in those of the mu agonist alfentanil or the kappa agonists [5R-(5,7,8,beta)]N-methyl-N-[7- (1-pirrolidinyl)1-oxaspiro[4,5]dec-8-yl]4-benzofuranaceta mide, bremazocine, ethylketocyclazocine and Mr2033. It is concluded that under the present conditions, nor-BNI acts as a selective kappa opioid antagonist with an extremely long duration of action. These findings are also consistent with the notion that nor-BNI may antagonize only compounds acting at a subtype of kappa opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Role of kappa opioid receptors during stress responsiveness in rats.

Effects of kappa opioid agonist, ketocyclazocine (KCZ) and its antagonist, M(r) 2266, were evaluated on some stress responses in rats. KCZ (1 or 10 mg/kg, ip) dose-dependently attenuated cold restraint stress (CRS)-induced gastric ulcer formation. Similar gastric cytoprotection was also seen with KCZ (1 or 10 micrograms/rat, icv). Pretreatment of rats with M(r) 2266 (0.3 mg/kg, ip) clearly antagonized the ulceroprotective effects of both ip and icv KCZ. KCZ effects on the gastric mucosa during CRS were also reduced by naltrexone (5 mg/kg, ip) pretreatment. KCZ (1 or 10 mg/kg, ip) also attenuated the plasma corticosterone response to CRS and these effects were blocked by M(r) 2266 (0.3 mg/kg) pretreatment. These results indicate kappa opioid receptor involvement during stress reactions and also suggest possible opioidergic interactions during CRS.

Animals↗
PubMed1993

Differential antagonism of bremazocine- and U69,593-induced antinociception by quadazocine: further functional evidence of opioid kappa receptor multiplicity in the mouse.

In these studies, the antagonistic actions of (-)-1-Cyclopentyl-5-(1,2,3,4,5,-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6 -methano-3-benzazocin-11-yl)-3-pentanone methanesulfonate (quadazocine) were evaluated against the kappa-receptor-mediated antinociceptive effects of i.c.v. (5 alpha, 7 alpha, 8 beta)-(+)-N-methyl-N-(7-(1-pyrrolidinyl)- 1-oxaspiro(4,5)dec-8-yl)benzeneacetamide (U69,593) or bremazocine in the mouse warm water tail-flick test. Quadazocine produced no antinociceptive effects alone, and it selectively antagonized the actions of bremazocine, but not U69,593, in a dose- and time-related fashion, supporting previous suggestions of differences in kappa receptors mediating the antinociceptive effects of these agonists. Quadazocine, however, also antagonized the antinociceptive effects of both DAMGO (opioid mu agonist) and DPDPE (opioid delta agonist) at doses approximately 3-fold less than those needed to attenuate significantly the effects of bremazocine. The structurally diverse kappa opioids (+-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b]- thiophene-4-acetamide (PD 117,302), ethylketocyclazocine (EKC) and tifluadom were studied under kappa-selective conditions, and the sensitivity of their effects to 1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-[2(1- pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-UPHIT] (kappa 1 antagonist) or quadazocine (kappa 2 antagonist) was determined. On this basis PD 117,302, EKC and tifluadom were classified as acting at opioid kappa 1, kappa 1, and kappa 2 receptors, respectively; EKC and tifluadom were also shown to have significant activity at opioid mu, but not delta, receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1996

Multiplicity of kappa opioid receptor binding in the rat cardiac sarcolemma.

In order to determine the opioid receptor binding in the rat cardiac sarcolemma, direct and displacement binding assays of tritiated bremazocine, a nonselective opioid, agonist and U69593, a specific kappa-receptor agonist, were performed in a sarcolemmal membrane preparation. Saturation studies revealed that there were substantial binding sites for both radioligands. The [3H]bremazocine had a binding capacity of 100 fmol/mg protein with a Kd of 3.4 nM while the binding of [3H]U69593 showed a Kd of 7.4 nM and a Bmax of 139 fmol/mg protein. Displacement binding assay showed that [D-Ala2, MePhe4, Gly-(ol)5]enkephalin (DAGO), a specific mu-agonist, exhibited no inhibitory effect on the binding of either [3H]bremazocine or [3H]U69593. [D-Ala2,D-Leu5]enkephalin (DADLE), a specific delta-agonist, had no inhibition on the binding of [3H]U69593, but displaced the binding of [3H]bremazocine at higher concentrations (10(-5)-10(-6)M). U50488, a specific kappa-agonist, completed with the binding of [3H]U69593 23 times more potently than with the binding of [3H]bremazocine. A residual binding sites of [3H]bremazocine was found with a Kd of 6.4 nM and a Bmax of 76 fmol/mg protein under conditions in which mu, delta and kappa 1 opioid bindings were suppressed by DAGO and DADLE at 200 nM and U50488 at 1 microM. DADLE at 5 microM, a concentration known to block kappa 2 binding sites, abolished the residual U50488-insensitive specific binding of [3H]bremazocine. Met5-Enkephalin-Arg6-Phe7, a specific kappa 2 ligand, displaced the binding of [3H]bremazocine much more readily than the binding of [3H]U69593. The present study provided evidence for the presence of two kappa-receptor subtypes in the cardiac sarcolemma: one U50488-sensitive and DADLE-insensitive, and the other U50488-insensitive and DADLE-sensitive. These two kappa-receptor binding subtypes may correspond to kappa 1 and kappa 2 receptor subtypes. Computer assisted non-linear regression analysis in the competition experiments of U50488 with [3H]U69593 afforded a best fit of the inhibition curves for two displacing components of kappa 1 binding sites: one with high affinity and low Bmax, another with low affinity and high Bmax.

Adenosine Triphosphatases↗
PubMed1996

Mechanism of clocinnamox blockade of opioid receptors: evidence from in vitro and ex vivo binding and behavioral assays.

In behavioral experiments, the cinnamoylaminomorphinone clocinnamox (CCAM) has been shown to act as an insurmountable antagonist of mu, but not delta or kappa opioid agonists. In contrast, CCAM displayed only moderate mu selectivity (29:6:1 for mu:delta:kappa) in radioligand displacement experiments using mouse brain membranes. In the present study, the apparent discrepancy between the high mu selectivity of the insurmountable functional antagonism of CCAM and its only moderate mu selectivity in in vitro binding experiments was resolved by in vitro washout experiments and ex vivo binding experiments involving all three opioid receptor types. In the ex vitro washout experiments, CCAM-mediated mu receptor binding inhibition could not be reversed even after allowing for 8 hr hr dissociation, whereas the CCAM inhibition of delta and kappa receptor binding was time-dependently reversed. In the ex vivo binding experiments, 1 hr pretreatment of mice with 10 mg/kg of CCAM i.p. decreased ex vivo [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin ([3H]DAMGO) binding (tested at > or = 5 * Kd) by 90%, paralleled by an 88% decrease in mu receptor density in equilibrium saturation binding assays. Ex vivo [3H]DAMGO binding returned to control levels with a T1/2 of 2.7 to 4.2 days (independent of the CCAM dose), the effect being predominantly due to a recovery of mu receptor density. The CCAM inhibition of ex vivo [3H]DAMGO binding was dose-dependent and could be prevented in part by simultaneous administration of the protein synthesis inhibitor cylcoheximide. In contrast to the ex vivo binding of [3H]DAMGO, ex vivo binding of p-[3H]CI-[D-Pen2, D-Pen5]enkephalin or (-)-[3H]bremazocine (in the presence of 1 microM DAMGO and 1 microM [D-Pen6, D-Pen5]enkephalin) was not affected by CCAM pretreatment. Finally, ex vivo [3H]DAMGO binding inhibition data correlated well with mu receptor population changes estimated by Black and Leff analysis of behavioral (antinociception) experiments (T1/2 of receptor reappearance, 3.2 days). Thus, although CCAM reversibly interacted with mu, delta and kappa opioid receptors, only binding to mu receptors was wash-resistant. Binding of methoclocinnamox, a codeinone CCAM precursor with mu agonistic activity, seemed to be at least partially reversible, even at mu receptors.

Animals↗
PubMed1997

Putative kappa-2 opioid agonists are antihyperalgesic in a rat model of inflammation.

It has been demonstrated that kappa-2 opioid receptor agonists can inhibit the current that flows through the N-methyl-o-aspartate (NMDA) subclass of excitatory amino acid receptor. NMDA receptor antagonists have been shown to be effective antihyperalgesic agents when administered intrathecally into rats. Antihyperalgesia is defined as the ability to block enhanced sensitivity, usually produced by nerve injury or inflammation, to nociceptive stimuli. Thus, the hypothesis was proposed that kappa-2 opioid receptor agonists would be antihyperalgesic when injected intrathecally into rats with an inflamed hind paw. The kappa agonists bremazocine and GR89,696 were effective at reversing the hyperalgesia associated with the inflamed hind paw but did not influence the sensitivity of the noninflamed hind paw to noxious heat. The kappa-1-selective agonist U69,593 had no effect on the heat sensitivity of either the inflamed paw or the noninflamed paw. Intrathecal injection of the mu-selective agonist [D-Ala2,N-MePhe4,Gly5-ol]enkephalin or the delta-selective agonist [D-Pen(2,5)]enkephalin elevated paw withdrawal latencies to heat in both hind paws. These findings indicate that activation of presumed kappa-2 receptors in the rat spinal cord results in suppression of the hyperalgesic state without influencing normal sensitivity to noxious stimuli. It is proposed that the antihyperalgesic effect of kappa-2 receptor activation is mediated by the ability of the opioid receptor to reduce the flow of current through the NMDA receptor ionophore.

Analgesics↗
PubMed1997

Kappa2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims.

Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry that affect motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blocking DA reuptake into the presynaptic nerve terminal, reciprocal signaling between DA and endogenous opioids has important implications for cocaine dependence. The present study used the opioid antagonist 6 beta-[125iodo]-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([125I]IOXY) after pretreatment with the site-directed acylating agents 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimid iazole -HCl (mu-selective) and N-phenyl-N-[1-(2-(4-isothiocyanato)-phenethyl)-4-piperidinyl]-p ropana mide-HCl (delta-selective) to examine the effect of cocaine exposure on the distribution and density of kappa2 receptors in autopsy studies of human cocaine fatalities. The selective labeling of the kappa2 receptor subtype was demonstrated by competition binding studies, which gave a pharmacological signature (IOXY >/= (+)-bremazocine >> U50,488 >/= U69,593) distinct from either the kappa1 or kappa3 receptor subtypes. Visualization of [125I]IOXY labeling revealed that kappa2 receptors localize to mesocortical and subcortical limbic areas, including the cingulate, entorhinal, insular, and orbitofrontal cortices and the nucleus accumbens and amygdala. The number of kappa2 receptors in the nucleus accumbens and other limbic brain regions from cocaine fatalities was increased twofold as compared with age-matched and drug-free control subjects. Cocaine overdose victims, who experienced paranoia and marked agitation before death, also had elevated densities of kappa2 receptors in the amygdala. These findings demonstrate for the first time that kappa2 receptor numbers are upregulated by cocaine exposure. The molecular adaptation of kappa2 receptor numbers may play a role in the motivational incentive associated with episodes of binge cocaine use and in the dysphoria that follows abrupt cocaine withdrawal.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

GR89,696 is a kappa-2 opioid receptor agonist and a kappa-1 opioid receptor antagonist in the guinea pig hippocampus.

Receptor binding studies and electrophysiological studies demonstrated the existence of at least two kappa opioid receptors, which have been designated kappa-1 and kappa-2. Several agonists and antagonists are selective for the kappa-1 receptor whereas no known ligands are selective for the kappa-2 receptor. In this study, the kappa opioid GR89,696 was tested in the guinea pig hippocampal slice preparation for kappa-1 versus kappa-2 activity. The perforant path-evoked population spike in the dentate was use to evaluate activity at the kappa-1 receptor, and the Schaffer collateral-evoked N-methyl-D-aspartate (NMDA) receptor-mediated synaptic current in CA3 pyramidal cells was used to measure kappa-2 receptor activation. GR89,696 had no effect on the perforant path-evoked dentate population spike; however, it did reverse the effects of the selective kappa-1 agonist U69,593 when co-perfused over the slices. In the CA3, GR89,696 inhibited the NMDA receptor-mediated synaptic current. The inhibition was antagonized by naloxone. The EC50 for GR89,696 on the NMDA current was 41.7 nM (95% CL, 7.0-248 nM). These findings indicate that GR89,696 is an agonist for kappa-2 opioid receptors and an antagonist at kappa-1 receptors in the guinea pig hippocampus.

Animals↗
PubMed1998

Tramadol, a centrally acting opioid: anticonvulsant effect against maximal electroshock seizure in mice.

The present study was designed to investigate the pro- or anticonvulsant effect of tramadol using maximal electroshock (MES) test. An attempt was also made to determine the possible opioid receptor mechanism involved. MES seizures were induced through transauricular electrodes (60 mA, 0.2s) and the seizure severity was assessed by the duration of tonic hindlimb extensor phase. Intraperitoneal (i.p.) administration of tramadol resulted in a dose-dependent anticonvulsant action; the ED50 for the effect was 33 mg/kg. The anti-MES effect of tramadol was antagonized by the low doses (0.05 and 0.1 mg/kg, s.c.) of MR 2266, a selective kappa receptor antagonist and also by the high doses (1.0 and 5.0 mg/kg, i.p.) but not the low doses (0.1 and 0.25 mg/kg) of naloxone. The results suggest that the anti-MES effect of tramadol is mediated by kappa receptors, since MR 2266 and naloxone (in high doses) are known to block these receptors.

Animals↗
PubMed1997

Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity.

The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.

Analgesics↗