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At least 19 recordsLinked to original sources
PubMed1984

Benzomorphan sites are ligand recognition sites of putative epsilon-receptors.

The binding characteristics of benzomorphan sites of rat brain membranes are compared with those of kappa-sites of human placenta and guinea pig brain membranes. Enkephalins and the stable analog [D-Ala2,D-Leu5]enkephalin, which are virtually inactive at kappa-sites, possess moderate binding affinity at benzomorphan sites. In contrast, a dynorphin analog, PL017-dynorphin A(6-17), binds well to kappa-sites but poorly to benzomorphan sites. Among all opioid peptides tested, beta h-endorphin, which is essentially inactive at the kappa-receptor sites, is the most potent ligand at benzomorphan sites. The potencies of beta h-endorphin and its fragments at epsilon-receptors of the rat vas deferens correlate well with their binding affinities of benzomorphan sites but not of mu- and delta-sites. These data, as well as the data which show the distinct distribution of benzomorphan sites in rat brain as compared with the distribution of mu- and delta-sites of rat brain and of kappa-sites of guinea pig brain, suggest that benzomorphan sites of rat brain are the ligand-binding sites of epsilon-receptors.

Animals↗
PubMed1995

Synthesis and sigma binding properties of 2'-substituted 5,9 alpha-dimethyl-6,7-benzomorphans.

The synthesis and sigma 1 and sigma 2 binding properties of several (+)- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9 alpha-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted-N-normetazocine), all (1S,5S,9S)-(+)-isomers showed higher affinity for the sigma 1 site than the corresponding (1R,5R,9R)-(-)-isomers. Replacement of the 2'-hydroxy group of (+)-2-benzyl-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1f] with a 2'-NH2 and 2'-N(CH3)2 [(+)-3b and (+)-3c, respectively] had only a small effect on the sigma 1 Ki values. Changing the 2'-hydroxy group of (+)-1f to an H, F, Cl, Br, I, NHAc, or NHSO2CH3 resulted in a 5-fold or greater loss in potency. In contrast, replacement of the 2'-hydroxy group of (+)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1b, (+)-pentazocine] with a 2'-H or 2'-F group resulted in a 2-fold increase in potency. Conversion of (+)-1f to its 2'-desoxy analogue (+)-2d resulted in a 27.5-fold loss in affinity. This suggests that (+)-1f and other N-substituted benzomorphan analogues may be binding to single sigma 1 receptors in a different way or to different sigma 1 receptors. (-)-Pentazocine [(-)-1b] and its 2'-fluoro analogue, (-)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-fluoro-6,7-benzomorphan [(-)-4a] showed the highest potency for the sigma 2 binding site.

Animals↗
PubMed1981

Novel opiate binding sites selective for benzomorphan drugs.

The simultaneous addition of [D-Ala2, D-Leu5]-enkephalin and morphiceptin at concentrations at which 98% of enkephalin (delta) and morphine (mu) receptors are occupied only partially inhibits the binding of [3H]diprenorphine to rat brain membranes. These conditions, furthermore, do not affect the curves for displacement of [3H]diprenorphine binding by unlabeled diprenorphine. These data suggest that [3H]diprenorphine binds to a third subtype of opiate binding site, which has high affinity for diprenorphine but very low affinity for mu and delta agonists. The [3H]-diprenorphine binding observed in the presence of morphiceptin and [D-Ala2, D-Leu5]enkephalin exhibits high affinity for several benzomorphan drugs in the chemical family of 6,7-benzomorphan (e.g., cyclazocine, ethylketocyclazocine, SKF 10047, UM 1072, oxilorphan, etc). Because of its selectivity for most benzomorphan drugs, this putative receptor site is tentatively referred to as a benzomorphan binding site. Its regional distribution in rat brain is similar to that of morphine (mu) receptors but differs from that for enkephalin (delta) receptors. The content of benzomorphan binding sites in rat brain is only one-half to one-third that of morphine receptors. The relative affinities of various opioids to morphine enkephalin, and benzomorphan binding sites are also described.

Animals↗
PubMed1983

Benzomorphan interactions with acetylcholine receptor complexes from Torpedo.

Benzomorphan interactions with acetylcholine receptor complexes from Torpedo californica electric organ were investigated using radiolabelled probes. All of the benzomorphans had minimal affinity for the acetylcholine binding site. Four benzomorphans (N-allylnormetazocine, cyclazocine, phenazocine and pentazocine) inhibited the binding of tritiated perhydrohistrionicotoxin and phencyclidine to ion channel sites with IC50 values between 0.4 and 5 microM. Two other benzomorphans, ketazocine and ethylketocyclazocine, were much less active. Thus, ion channel affinity is not limited to benzomorphans which stimulate sigma-opiate receptors, and is not a certain indication of psychotomimetic potency.

Amphibian Venoms↗
PubMed1981

Distinct high-affinity binding sites for benzomorphan drugs and enkephalin in a neuroblastoma--brain hybrid cell line.

The high-affinity binding of benzomorphan drugs (ethylketocyclazocine and N-allylnorcyclazocine) and [DAla2,DLeu5] enkephalin was examined in a mouse neuroblastoma--Chinese hamster brain clonal hybrid cell line (NCB-20). Scatchard analysis of saturation binding isotherms indicated the presence of a single binding site for 3H-labeled [DAla2,DLeu5]enkephalin (Kd = 3 nM) and multiple binding sites for [3H]ethylketocyclazocine (Kd = 4 and 20 nM) and N-[3H]allylnorcyclazocine (Kd = 0.5 and 15 nM). Both ethylketocyclazocine and N-allylnorcyclazocine competed (Ki = 10 and 30 nM, respectively) with [3H][DAla2,DLeu5]enkephalin binding in NCB-20 cells but neither [DAla2,DLeu5]enkephalin nor morphine could completely inhibit the specific binding of [3H]ethylketocyclazocine (7 nM) or N-[3H]allylnorcyclazocine (3 nM). Furthermore, not all benzomorphan drugs (e.g., ethylketocyclazocine) were totally efficacious in displacing 3 nM N-[3H]allylnorcyclazocine binding in the presence or absence of high concentrations of [DAla2,DLeu5]enkephalin. The data presented suggest that benzomorphan drugs interact with three distinct high-affinity binding sites: (i) a site that binds enkephalin and morphine in addition to ethylketocyclazocine and N-allylnorcyclazocine; (ii) a site that binds both ethylketocyclazocine and N-allylnorcyclazocine but not enkephalin and morphine; and (iii) a site that binds N-allylnorcyclazocine but not enkephalin, morphine, or ethylketocyclazocine. The first of these sites was comparable to the delta opiate receptor expressed in NG108-15 and N4TG1 cell lines based on the potency series obtained for various opiates and benzomorphan drugs in competition studies with [3H][DAla2,DLeu5]-enkephalin. However, the specific high-affinity benzomorphan binding sites thus far are unique and may represent biochemical correlates of kappa and sigma opiate receptors which have been proposed to exist on the basis of physiological studies.

Analgesics, Opioid↗
PubMed1975

Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey.

1 Four benzomorphans which have potent antinociceptive activity in the hot-plate and writhing tests in the mouse but do not suppress or precipitate withdrawal symptoms in the morphine-dependent monkey, have been examined for their pharmacological actions in the guinea-pig ileum and mouse vas deferens. 2 In the guinea-pig ileum their agonist potencies are 1.5 to 400 times greater than that of normorphine of morphine whereas in the mouse vas deferens their potencies relative to morphine are 0.3 to 100. They exhibit no antagonist activity in either preparation. Benzomorphans which substitute for morphine in the morphine-dependent monkey do not show such differences between their relative potencies in the guinea-pig ileum and mouse vas diferens. 3 The relative potencies of the four benzomorphans to inhibit stereospecific [3H]-dihydromorphine binding by membrane fragments from rat brain, are more closely related to their relative agonist potencies in the mouse vas deferens than to those found in the guinea-pig ileum. 4 In order to antagonize the agonist actions of these benzomorphans, naloxone is required in concentrations which are 3 to 7 times higher than those needed for the antagonism of normorphine or morphine or of benzomorphans which suppress abstinence in morphine-dependent monkeys. 5 It may be possible to use the three assays, namely, ratio of relative agonist potency in mouse vas deferens to that in guinea-pig ileum, ratio of relative agonist potency to relative affinity to opiate receptors and the concentration of nalozone required for antagonism, for the prediction of the potential of new compounds to produce physical dependence.

Analgesics, Opioid↗
PubMed1993

Similar ameliorating effects of benzomorphans and 5-HT2 antagonists on drug-induced impairment of passive avoidance response in mice: comparison with acetylcholinesterase inhibitors.

Mice were trained to avoid electric shocks by means of step-down type passive avoidance learning tasks, and memory retention was measured 24 h after the training session. Memory impairment (amnesia) was produced by administering either p-chloroamphetamine (PCA), a serotonin (5-HT) releaser or scopolamine (SCOP), a muscarinic cholinoceptor antagonist, 30 min prior to the training session. Benzomorphans, 5-HT2 antagonists and acetylcholinesterase (AChE) inhibitors were administered immediately after the training session. PCA- but not SCOP-induced amnesia was attenuated by the post-training administration of two benzomorphans, (+)N-allylnormetazocine ((+)SKF-10,047) and (+/- )pentazocine ((+/- )PTZ). Similarly, PCA-induced amnesia was reversed by the post-training administration of 5-HT2 antagonists, ritanserin (RIT) and mianserin (MIA), but SCOP-induced amnesia was not. However, the AChE inhibitors, tetrahydroaminoacridine (THA) and physostigmine (PHY) attenuated both PCA- and SCOP-induced amnesia when administered immediately after the training session. These results indicated that benzomorphans and 5-HT2 antagonists have antiamnestic effects in mice, as do AChE inhibitors. In addition, it is interesting that the patterns of ameliorating effect of benzomorphans were similar to those of 5-HT2 antagonists, which differ from those of AChE inhibitors.

Acetylcholine↗
PubMed1995

Evaluation of a series of N-alkyl benzomorphans in cell lines expressing transfected delta- and mu-opioid receptors.

Transfection of individual opioid receptors in Chinese hamster ovary (CHO) cells provides a pure, homogeneous population of receptors for screening drug candidates, and an alternative to the use of selective ligands. To evaluate the potential of this system, we chose a series of (-)-5,9 alpha-dimethyl-2-hydroxy-N-substituted-6,7-benzomorphans, for which the receptor selectivity and in vivo activity had been characterized recently, and tested them in CHO cells stably transfected with either the rat delta-opioid receptor or the mouse mu-opioid receptor. [3H]Diprenorphine was used to measure opioid receptors in P2 membrane preparations. A Bmax of 7.58 +/- 0.8 pmol/mg protein and a Kd of 0.42 +/- 0.04 nM was obtained in the mu-opioid receptor expressing cell line used in these studies. In addition, [3H]naltrindole was used to confirm the delta-specificity of the cloned receptor. Both compounds gave a Bmax of 1.2 pmol/mg in the CHO cells expressing the rat delta-opioid receptor. Displacement assays were performed with eleven (-)-N-alkyl-benzomorphans in the absence and presence of 150 mM NaCl, as well as known delta- and mu-selective agonists. Sodium reduced agonist affinity in the transfected cell lines. The benzomorphan compounds displayed a range of affinities in the mu- and delta-opioid receptor expressing cell lines. Good correlations were found between their affinities at the cloned mu- and delta-opioid receptors and those in rat brain and monkey cortex (r2 from 0.73 to 0.89, P < 0.001). Comparative analysis of Ki values with in vivo potency in the mouse tail flick test indicated a high degree of correlation between antinociception and affinity in the mu-opioid receptor cell line (r2 = 0.83, p < 0.0001). Lesser correlations were found between antinociception in the mouse and affinity at the rat mu-opioid receptor (r2 = 0.6610) and at the monkey mu-opioid receptor (r2 = 0.695). In sum, these studies indicate that the cell lines expressing the cloned mu- and delta-opioid receptors are appropriate models for determining the binding affinities of this class of opioid compounds. The diminishing correlations found between species when comparing in vitro and in vivo activity suggest that caution should be taken when extrapolating binding data to pharmacological activity among species.

Animals↗
PubMed1990

A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain.

Two highly selective radiolabeled probes for sigma receptors were found to bind with high affinity and capacity to membranes from undifferentiated PC12 cells. [3H]1,3-di-o-tolylguanidine [( 3H]DTG) bound with Kd = 23.7 +/- 4.6 nM and Bmax = 2025 +/- 660 fmol/mg protein. The Kd and Bmax for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) were 86.3 +/- 21.6 nM and 1539 +/- 242 fmol/mg protein, respectively. These binding parameters were comparable to those observed in guinea pig brain, although the Kd for [3H](+)-3-PPP was 3-fold higher in the PC12 membranes. Both the PC12 and guinea pig brain sites exhibited high affinity for haloperidol, moderate affinity for phencyclidine (PCP), and negligible affinity for MK-801, apomorphine, and (-)-sulpiride. These data suggest a relationship of the PC12 site to sigma receptors. However, all (+)-opiates [+)-benzomorphans and (+)-morphinans) tested bound with markedly lower affinity to the PC12 site compared to guinea pig brain. These include (+)-N-allylnormetazocine [+)-SKF 10,047), (+)-pentazocine, and dextrallorphan. In fact, PC12 sites exhibited preference for (-)-benzomorphans, the reverse stereoselectivity of guinea pig brain sites. Binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) could not be detected, demonstrating absence of PCP receptors on this cell line. Differentiation of cells by treatment with nerve growth factor had no effect on sigma binding parameters. Membranes from guinea pig brain and PC12 cells were photoaffinity-labeled using [3H]azido-di-o-tolylguanidine. In guinea pig brain, a polypeptide of 25 kDa was specifically labeled. However, label was incorporated into polypeptides of 18 kDa and 21 kDa in membranes from PC12 cells. In view of the otherwise similar binding characteristics, the marked differences in affinity for (+)-benzomorphans and molecular weight suggest that PC12 cells contain a molecular form of sigma receptor distinct from that predominant in guinea pig brain. This raises the possibility of multiple sigma receptor types.

Adrenal Gland Neoplasms↗
PubMed1985

Autoradiographic localization of benzomorphan binding sites in rat brain.

The benzomorphan subpopulation of opiate binding sites was labeled by [3H]diprenorphine in the presence of unlabeled ligands selected to quench mu and delta opiate binding sites. The distribution of benzomorphan binding sites was then localized autoradiographically. Areas particularly enriched in these sites were nucleus solitarius, nucleus ambiguus, substantia gelantinosa of the trigeminal nerve, the habenula, and the medial nucleus of the amygdala. Within hippocampal formation, binding was relatively enhanced in the pyramidal and granule cell layers. Within the basal ganglia, binding was greatest in the dorsomedial caudate nucleus and least in the globus pallidus. No 'patches' of increased binding were present in the striatum. The interstitial nucleus of the stria terminalis and the medial preoptic nucleus also showed significant binding. This distribution differs from the distributions of mu, delta and kappa opiate binding and is quite similar to the distribution of beta-endorphin immunoreactivity. These observations support the hypothesis, based on biochemical studies in brain membranes, that benzomorphan binding sites may represent the ligand recognition sites of putative epsilon receptors.

Animals↗
PubMed1976

Synthesis and pharmacology of 2,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan.

2,9alpha-Dimethyl-2'-hydroxy-6,7-benzomorphan (14) has been synthesized in six to seven steps from trans-3,4-dihydro-4-(2-dimethylaminoethyl)-6-methoxy-3-methyl-1(2H)-naphthalenone (1). The key reaction of the sequence was mercuric acetate cyclization of trans-1,2-dihydro-1-(2-methylaminoethyl)-7-methoxy-2-methylnaphthalene (8) which gave a mixture of 9alpha-methyl-8alpha-hydroxy-6,7-benzomorphan (9, 49%), the corresponding acetate (10, 13%), and the 9beta-methyl-8alpha-hydroxy-6,7-benzomorphan (11, 5%). In the presence of Et3N, the yields were 16, 37, and 0%, respectively. Structural assignments are based on ir, NMR, and mass spectral data and on chemical conversions.

Analgesics↗
PubMed1976

Opiate receptor interactions of benzomorphans in rat brain homogenates.

Minor structural variations of benzomorphans opiates are associated with striking, unpredictable shifts in the relative extent of agonist or antagonist properties in vivo. The relative abilities of a number of benzomorphans in inhibit 3H-naloxone binding in the absence and presence of sodium in vitro show some correlations with their pharmacologic properties in vivo, although distinct exceptions exist. The ability of opiate agonists to inhibit 3H-naloxone binding is greatly reduced by sodium, while pure antagonists are affected very little, if at all, and mixed agonist-antagonist benzomorphans display an intermediate response.

Animals↗
PubMed1985

In vivo binding of benzomorphans to mu, delta and kappa opioid receptors: comparison with urine output in the rat.

In vivo binding affinities of three benzomorphans, Win 44,441-3, bremazocine and MR 2266, were determined at the mu, delta and kappa types of opioid binding sites in rat brain, using an ex vivo labeling technique. The receptor occupancy of the benzomorphans and of previously tested diprenorphine were compared with their activities in increasing urine output (agonist ED50: bremazocine) or inhibiting bremazocine-induced diuresis (antagonist ID50: Win 44,441-3, MR 2266 and diprenorphine). The agonist, bremazocine, bound (in order of decreasing affinity) to the kappa approximately equal to mu greater than delta binding sites, and it's pharmacological effects appeared in the dosage range of kappa and mu binding. In order to positively identify which receptor type is responsible, the potency of the three antagonists to block the effects of bremazocine were compared to their ability to occupy the individual sites in vivo. A fractional occupancy of 0.5 would be expected at the ID50 if one assumes a linear relationship between receptor occupancy by the antagonist and the antagonistic effect. Such a linear relationship was observed for the three antagonists only at the kappa site, whereas variable occupancies were observed at the mu and delta sites. These results support the previously proposed hypothesis that kappa receptors mediate the effects of benzomorphan opioid drugs on urine flow.

Animals↗
PubMed1984

In vivo evidence for benzomorphan-selective receptors in rats.

The scratching caused by a standard, submaximal dose of bombesin (0.10 microgram i.c.v.) in rats is antagonized in a stereospecific and dose-related manner by systemically (but not centrally) administered benzomorphan analgesics; other commonly used opioids and opioid peptides are ineffective at behaviorally nondepressent doses. Naloxone attenuates the antibombesin effect of ethylketocyclazocine in a stereospecific, potent and dose-related manner. Tolerance develops to the inhibitory action of ethylketocyclazocine (and phenazocine). Multiple injections of morphine do not influence the ability of ethylketocyclazocine or of phenazocine to antagonize bombesin. Furthermore, when mu opiate receptors are occluded by buprenorphine, ethylketocyclazocine and phenazocine can still antagonize bombesin-induced scratching. Benzomorphan-selective binding sites have previously been postulated; we suggest that this test provides evidence of such sites in vivo. The model affords a simple, yet novel, behavioral endpoint that can be used when defining the pharmacological profile of new benzomorphans and their antagonists.

Analgesics, Opioid↗
PubMed1982

Synthesis and pharmacological studies of 2'-sulphonyl[3-(3H-2,4-disubstituted-1,5-benzodiazepino)]-2,5-dimethyl-6,7-benzomorphans.

2'-Sulphonyl[3-(3H-2,4-dimethyl-1,5-benzodiazepino)]-2,5-dimethyl-6,7-ben zomorphan (3a), 2'-sulfonyl[3-(3H-2 methyl-4-phenyl-1,5-benzodiazepino)]-2,5-dimethyl-6,7-benzomorphan (3b) and 2'-sulfonyl [3-(3H-2-methyl-4-oxo-5H-1.5-benzodiazepino)]-2,5-dimethyl-6,7-benzomorphan (3c), synthesized from 2,5-dimethyl-6,7-benzomorphan (1) in three steps via chlorosulphonation, condensation with sodium salt of acetylacetone, benzoylacetone and ethyl acetoacetate separately and condensation with o-phenylenediamine, were studied for their pharmacological activities. It was found that 3a has mild CNS depressant, analgesic and anticonvulsant (against petit mal type of seizures) activities. 3b has significant anti-depressant and mild analgesic activities while 3c has CNS depressant, mild analgesic and anticonvulsant activities (against petitmal type seizures).

Analgesics↗
PubMed1987

2,5-Dimethyl-2'-hydroxy-9 alpha- and 9 beta-(3-methylbutyl)-6,7-benzomorphans and N-substituted compounds in the 9 alpha-(3-methylbutyl) series: chemistry, pharmacology, and biochemistry.

2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9 alpha-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.

Analgesics↗
PubMed1991

(+)-6,7-benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue.

The benzomorphan sigma ligands, (+)-N-allylnormetazocine (NANM) and (+)-pentazocine, but not (+)-cyclazocine, stereospecifically stimulated dopamine synthesis in minces of rat corpus striatum by 15-23% over basal values at 0.1-1.0 microM. The effect of (+)-NANM and (+)-pentazocine was blocked by the reported sigma antagonist, BMY-14802 but not by the opiate antagonist naloxone. These results suggest that these (+)-benzomorphans may act as agonists at putative sigma heteroreceptors on striatal nerve terminals, or through an indirect mechanism, to modulate dopamine synthesis.

Animals↗
PubMed1982

Benzomorphan binding sites in rat lumbo-sacral spinal cord.

The rat lumbo-sacral spinal cord contains a homogeneous population of opiate binding sites labelled with high affinity (KD = 0.21 +/- 0.04 nM) by [3H]etorphine and lower affinity (KD = 2.2 +/- 0.4 nM) by [3H]ethylketocyclazocine. Benzomorphan drugs are potent competitors for these binding sites while morphine and enkephalin display a low affinity. These binding sites have binding properties which are distinct from the mu-, delta-, and also kappa-sites but are very similar to those of the benzomorphan sites characterized in rat brain.

Animals↗