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PubMed1991

Identification and characterization of two sigma-like binding sites in the mouse neuroblastoma x rat glioma hybrid cell line NG108-15.

NG108-15 cells were shown to possess high affinity binding sites for 1,3-di(2-[5-3H]tolyl)guanidine ([3H]DTG), a selective sigma ligand (Kd = 23 nM; maximal number of binding sites = 15.6 pmol/mg). The rank order of potency of drugs at this site was DTG greater than haloperidol greater than pentazocine greater than 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] greater than phencyclidine (PCP) greater than metaphit greater than (-)-3-PPP greater than (-)-N-allylnormetazocine [(-)-SKF 10,047] greater than (-)-butaclamol greater than (+)-butaclamol greater than (+)-SKF 10,047 greater than dizolcipine (MK 801 [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine- maleate]) greater than ketamine. Both, Kd value and pattern of ligand selectivity suggest a close relationship to sigma sites in rodent brain. However, in comparison to sigma sites in brain stereoselectivity for the benzomorphan, SKF 10,047 was reversed and the affinities for benzomorphans were only moderate to low. Thus, sigma binding sites in NG108-15 cells seem to correspond to recently detected sigma sites in a pheochromocytoma cell line (PC12). [3H]-1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP), a PCP receptor-selective ligand binds to NG108-15 cells with moderate affinity (Kd = 139 nM; maximal number of binding sites = 4.7 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Receptor site topographies for phencyclidine-like and sigma drugs: predictions from quantitative conformational, electrostatic potential, and radioreceptor analyses.

Computer-assisted molecular modelling techniques and electrostatic analyses of a wide range of phenycyclidine (PCP) and sigma ligands, in conjunction with radioreceptor studies, were used to determine the topographies of the PCP and sigma receptors. The PCP receptor model was defined using key molecules from the arylcyclohexylamine, benzomorphan, bridged benz[f]isoquinoline, and dibenzocycloalkenimine drug classes. Hypothetical receptor points (R1, R2) were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor, along with an additional receptor point (R3) representing a hydrogen bond between the nitrogen atom and the receptor. The superimposition of these key molecules gave the coordinates of the receptor points and nitrogen defining the primary PCP pharmacophore as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.66, -1.13, 0.00), and N (3.90, -1.46, -0.32). Additional analyses were used to describe secondary binding sites for an additional hydrogen bonding site and two lipophilic clefts. Similarly, the sigma receptor model was constructed from ligands of the benzomorphan, octahydrobenzo[f]quinoline, phenylpiperidine, and diphenylguanidine drug classes. Coordinates for the primary sigma pharmacophore are as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.09, 2.09, 0.00), and N (4.9, -0.12, -1.25). Secondary binding sites for sigma ligands were proposed for the interaction of aromatic ring substituents and large N-substituted lipophilic groups with the receptor. The sigma receptor model differs from the PCP model in the position of nitrogen atom, direction of the nitrogen lone pair vector, and secondary sigma binding sites. This study has thus demonstrated that the differing quantitative structure-activity relationships of PCP and sigma ligands allow the definition of discrete receptors. These models may be used in conjunction with rational drug design techniques to design novel PCP and sigma ligands of high selectivity and potency.

Animals↗
PubMed1984

[3H]Ethylketocyclazocine binding to mouse brain membranes: evidence for a kappa opioid receptor type.

The binding of the putative kappa agonist ethylketocyclazocine (EKC) to synaptosomal membranes of mouse brain was studied. This benzomorphan was able to bind to different opioid receptors. A portion of this binding was not inhibited by the agonist naloxone, even at high concentrations (10 microM). This population of receptors, to which opioate alkaloids and opiod peptides display very low affinity, is probably the sigma receptor. Another class of binding sites was identified by the simultaneous addition of the selective agonists Sandoz FK-33824 and D-Ala2-D-Leu5-enkephalin, which blocked the access of EKC to mu and delta opioid receptors, respectively, leaving a portion of naloxone-displaceable benzomorphan binding still detectable. Analysis of this remaining binding revealed a small population of receptors of high affinity, the kappa receptor. Therefore, EKC binds to the mu, delta, kappa and sigma receptors in the mouse brain, with similar affinities for the mu and kappa (0.22 and 0.15 nM). These results confirm the existence of a kappa opioid receptor type in the mouse brain.

Animals↗
PubMed1984

A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metabolism in vivo.

Phencyclidine [(l-phenylcyclohexyl) piperidine] (PCP) is known to increase the basal efflux of striatal dopamine (DA) in vitro and to enhance haloperidol (HAL)-induced striatal DA metabolism in vivo. This study compared these activities of PCP to several representatives of the arylcyloalkylamine, benzomorphan and substituted dioxolane classes whose behavioral similarities to PCP have been well studied. The affinity of these drugs for the PCP/sigma opiate receptor also was estimated by determining the concentration of these drugs required to inhibit the specific binding of 10 nM [3H]PCP to rat cortical membranes by 50%. Of the arylcycloalkylamines tested on the basal efflux of [3H]DA, we found the rank-order effectiveness to be as follows: PCP greater than 1-[l-(napthyl)cyclohexyl]piperidine HCl (m-amino-PCP) greater than ketamine greater than or equal to 1-[l-(m-nitrophenyl)cyclohexyl]piperidine HCl (m-nitro-PCP) greater than N-ethyl-l-phencyclohexylamine (PCE). However, in vivo we found that PCP, m-amino-PCP and PCE significantly elevated HAL-induced DA metabolism, whereas ketamine and m-nitro-PCP were without effect. Although each of the benzomorphans tested [N-allylnormetazocine (NANM) and ethylketocyclazocine (EKC)] slightly enhanced the basal efflux of [3H]DA from striatal slices, concentrations of 10 to 30 microM were required to elicit the same magnitude of [3H]DA release caused by 3 microM PCP. Quantitatively similar responses were produced by the substituted dioxolanes tested (etoxadrol, dexoxadrol and levoxadrol). Neither (+)-NANM, (-)-NANM, (+/-)-NANM, etoxadrol nor dexoxadrol had any effect on HAL-induced DA metabolism. On the other hand, both levoxadrol and EKC significantly decreased the ratio of HVA/DA after HAL administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

[3H]ethylketocyclazocine binding to NCB-20 hybrid neurotumor cells.

Ethylketocyclazocine (EKC) binds to two sites on NCB-20 neuroblastoma X Chinese hamster brain hybrid cells (KDH = 2 nM, Bmax = 21,000 sites/cell; KDL = 27 nM, Bmax = 140,000 sites/cell. The high-affinity site has been characterized as a delta opiate receptor. The low-affinity site is relatively benzomorphan-specific; opioid peptides, morphine, etorphine, and naloxone do not compete at it. Rank order of potency among benzomorphans is (+)-EKC greater than Mr 2267 greater than (+)-ketocyclazocine greater than (+)-SKF 10047 greater than bremazocine greater than cyclazocine. Among other drugs of interest that inhibit [3H]EKC binding are phencyclidine and its analogues, Ki values for which are 0.2-40 microM. Stereoselectivity is the reverse of other opioid receptors: (+)-EKC much much greater than (-)-EKC, Mr 2267 greater than Mr 2266, (+)-SKF 10047 greater than (-)-SKF 10047. The site is sensitive to trypsin, but not to N-ethylmaleimide. Binding is insensitive to nucleotides, slightly sensitive to physiological concentrations of sodium, magnesium, and manganese ions and to EDTA but not EGTA.

Animals↗
PubMed1981

Interactions of narcotics an their antagonists with human serum esterase. IX: structure-activity relationships of morphinans and morphines.

The interaction of 21 morphinan and 25 morphine derivatives with human serum esterase was examined. The behavior of these drugs closely parallels that of their simpler analogues, benzomorphans, studied previously: all have affinity for an allosteric modifying site at which agonists accelerate enzyme action and, except for 6-ketodihydromorphines, all are also competitive inhibitors of the enzyme. The results suggest that both ring C of morphinans and morphines and the furan ring of morphines contribute to binding to the allosteric site; so does increase in the size of the N-alkyl group, but alkylation at C-6 or C-7 is unfavorable for such binding. A hydroxyl group at C-6 or C-14, or a methoxyl group at C-3 are also unfavorable. As with benzomorphans, we found that the natural (--)-morphine configuration is more sensitive than its optical antipode to structural influences on its affinity for the allosteric site.

Chemical Phenomena↗
PubMed1995

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability.

The morphological effects of several neuroleptics as well as other novel and prototypic sigma ligands were examined by addition to cultures of C6 glioma cells. Sigma ligands caused loss of processes, assumption of spherical shape, and cessation of cell division. The time course and magnitude of this effect were dependent on the concentration of sigma ligand. Continued exposure to sigma compounds ultimately resulted in cell death. However, the morphological effect was reversible when sigma ligand was removed shortly after rounding. The potency of compounds to produce these effects generally correlated with binding affinity at sigma receptors of C6 glioma cell membranes labeled with [3H](+)-pentazocine. At a concentration of 100 microM, haloperidol, reduced haloperidol, fluphenazine, perphenazine, trifluoperazine, BD737, LR172, BD1008, and SH344 produced significant effects in 3-6 hr of exposure. Other compounds, such as trifluperidol, thioridazine, and (-)-butaclamol, produced significant effects by 24 hr of exposure. Despite the requirement of micromolar concentrations of ligand (some compounds were effective at 30 microM), the effect showed a remarkable specificity for compounds exhibiting sigma receptor binding affinity. Neuroleptics lacking potent sigma affinity [e.g., (-)-sulpiride, (+)-butaclamol, and clozapine] and other compounds that lack significant sigma affinity but that are agonists or antagonists at dopamine, serotonin, adrenergic, glutamate, phencyclidine, GABA, opiate, or muscarinic cholinergic receptors were without effect on cellular morphology at concentrations up to 300 microM over a period of 72 hr. Likewise, blockers and activators of Na+, K+, and Ca2+ channels and a monoamine oxidase inhibitor devoid of sigma affinity were without effect. Interestingly, 1,3-di-o-tolylguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP], (+)-pentazocine, (+)-cyclazocine, and other sigma-active benzomorphans and morphinans appeared inactive in up to 72 hr of culture. However, these compounds interacted synergistically with a subeffective dose of BD737 (30 microM) to produce effects usually in 6 hr or less. Also, the pH of the culture medium had a profound effect on the activity of sigma compounds. Increasing the pH from the normal range of 7.2-7.4 to pH 8.3-8.5 shifted the dose curves (30, 100, 300 microM) for all sigma compounds to the left. Under these conditions, DTG, (+)-3-PPP, and benzomorphans produced effects in 24 hr or less.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

kappa-Opioid receptor binding populations in rhesus monkey brain: relationship to an assay of thermal antinociception.

The binding characteristics of the kappa opioid ligands [3H]U69,593 and [3H]bremazocine, the mu opioid ligand [3H][D-ala2,N-Me-Phe4,glycol5]enkephalin and the delta opioid ligand [3H]p-Cl-[D-pen2,5]enkephalin were studied in rhesus monkey brain membranes in saturation binding experiments and were followed by competition binding experiments with a variety of peptidic and nonpeptidic opioid ligands. The [3H]U69,593 sites appeared to be a subset of kappa opioid receptors (kappa-1 receptors: Kd, 1.2 nM; Bmax, 66 fmol/mg). [3H]Bremazocine (in the presence of mu and delta receptor-masking agents), bound to a larger population of kappa receptors (kappa-all: Kd, 0.39 nM; Bmax, 227 fmol/mg), which presumably included the aforementioned kappa-1 sites. Competition binding experiments revealed that the presently defined kappa-1 sites were similar to previously reported sites in other mammalian species, particularly in terms of the higher kappa-1 selectivity observed with arylacetamide (e.g., U50,488) vs. benzomorphan kappa agonists (e.g., ethylketocyclazocine). The kappa-selective antagonist norbinaltorphimine (nor-BNI) displayed a very small (2.3-fold) selectivity for kappa-1 vs. kappa-all sites. This led to the prediction that in rhesus monkeys (n = 3), systemically administered nor-BNI (10 mg/kg s.c.) should have a very moderate degree of antagonist selectivity for the antinociceptive effects of a putative kappa-1-agonist, the arylacetamide U50,488 (0.1-3.2 mg/kg s.c.), vs. those of the benzomorphan kappa agonist ethylketocyclazocine (0.01-056 mg/kg s.c.). This prediction was confirmed in vivo because nor-BNI (10 mg/kg) caused a robust and long lasting (up to 21 days) antagonism of the antinociceptive effects of U50,488 and a small but significant antagonism of ethylketocyclazocine. The arylacetamide congener Cl-977 (enadoline), which displayed an 11-fold kappa-1 vs. kappa-all binding selectivity, was not sensitive to nor-BNI pretreatment. This indicates that the kappa subtype-binding profile of an agonist is not necessarily predictive of its sensitivity to nor-BNI in vivo. Overall, the present results suggest that at least two functional kappa receptor populations may be present in rhesus monkey brain.

Analgesics, Opioid↗
PubMed1976

Comparison of withdrawal precipitating properties of various morphine antagonists and partial agonists in relation to their stereospecific binding to brain homogenates.

In morphine-dependent rats the withdrawal precipitating properties of various morphine antagonists and partial agonists were studied by quantitatively evaluating a variety of different withdrawal signs. A comparison of the dose response curves of the various substances obtained for the different signs revealed marked differences in respect to the lowest effective doses (EDs) necessary to precipitate the withdrawal signs as well as in the maximum frequencies of the signs induced. The "pure" antagonist, naloxone, which was judged very potent according to the ED, precipitated the lowest levels of jumping, whereas certain partial agonists of the benzomorphane type, which were less potent according to the ED, induced very high levels of this sign. These latter compounds, however, failed to precipitate "complete" withdrawal, as evidenced by the nearly complete absence of some of the withdrawal signs. The jumping precipitating potency of the antagonists as judged from the ED was found to be highly correlated to the stereospecific binding of these substances to rat brain homogenate. On the other hand, the ability of the substances to precipitate high levels of jumping was seen to increase, at least within a certain range, with increasing degree of agonistic properties, as indicated by the ratio of stereospecific binding in the presence and absence of sodium.

Benzomorphans↗
PubMed1976

Induction of physical dependence in rats by short interval medication.

Rats were intermittently medicated at one hour intervals through an implanted intravenous cannula. Physical dependence on morphine and codeine was developed rapidly and it was detectable with the maintenance dose as low as 9.6 mg/kg/day. Physical dependence on pentazocine was also developed with the maintenance dose of 96 mg/kg/day, but was not with 9.6 mg/kg/day. In the pentazocine-treated rates, body weight loss was observed after the abrupt withdrawal, and abstinence signs were precipitated by naloxone 1 mg/kg. Cross physical dependence between morphine and pentazocine was demonstrated. Pentazocine suppressed the abstinence signs of rats weakly dependent on morphine, and morphine suppressed those of pentazocine-dependent rats. ID-1229, a new benzomorphan analgesic, did not produce dependence in this test and did not suppress the abstinence signs of morphine- and pentazocine-dependent rats.

Animals↗
PubMed1984

The involvement of mu- and kappa- but not delta-opioid receptors in the body weight gain of suckling rats.

The effects of the benzomorphan antagonist Mr 2266 and the selective delta-antagonist ICI 154,129 on the body weight gain of 6-day-old suckling rat pups was observed. Mr 2266 significantly reduced body weight gain in these animals, though ICI 154,129 had no affect on this variable. These findings suggest that mu- and kappa- but probably not delta-opioid receptors are involved in the regulation of ingestive behaviours in infant rats. The results are discussed in relation to the development of opioid-receptor subtypes in the neonatal rat brain.

Animals↗
PubMed1986

Presynaptic opioid receptors modulating acetylcholine release in the hippocampus of the rabbit.

Slices of the rabbit hippocampus were preincubated with 3H-choline, rinsed and superfused continuously. The release of 3H-acetylcholine in these slices, evoked by electrical field stimulation, was strongly reduced by the preferential kappa-agonists ethylketocyclazocine, dynorphin A (1-13) and dynorphin A (1-17). Dynorphin A (1-9) and (-)MR 2034 [(-)5,9-dimethyl-2'-OH-2-tetrahydrofurfuryl-6, 7-benzomorphan] were less potent, the (+)enantiomer of (-)MR 2034 was ineffective. Whereas the mu-agonist DAGO (D-Ala2-Gly-ol5-enkephalin) showed significant depressant effects, two other mu-agonists morphine and morphiceptine, as well as the delta-agonists DADLE (D-Ala2-D-Leu5-enkephalin) and Leu-enkephalin were much less inhibitory. The preferential mu-antagonist (-)naloxone as well as (-)MR 2266 [(-)N-(3-furylmethyl)-alpha-noretazocine], a preferential kappa-antagonist, did not increase acetylcholine release when given alone, but antagonized the effect of ethylketocyclazocine; (-)MR 2266 (Ke: 1.6 nmol/l) was about 4 times more potent than (-)naloxone (Ke: 6.3 nmol/l). The inhibitory effects of DAGO and DADLE were abolished by (-)MR 2266 (0.1 mumol/l) but not by the delta-antagonist ICI 174864 (N,N-diallyl-Tyr-Aib-Phe-Leu-OH, 0.3 mumol/l). It is concluded that the release of acetylcholine in the hippocampus of the rabbit is inhibited at the level of the axon terminals via kappa-receptors; in addition, mu-receptors may be present. An inhibitory tone of endogenous opioid peptides on hippocampal acetylcholine release could not be demonstrated. Experiments on rat hippocampal slices showed that in this species mu- rather than kappa-receptors may modulate acetylcholine release.

Acetylcholine↗
PubMed1999

Bremazocine reduces unrestricted free-choice ethanol self-administration in rats without affecting sucrose preference.

It has been postulated that opioid systems in the brain may play a role in ethanol reinforcement. In this respect, mu- and delta-opioid receptors may mediate the rewarding effects whereas kappa receptors are thought to mediate the aversive effects of opioids. Accordingly, long-acting benzomorphans such as bremazocine, that simultaneously act as mu and delta receptor antagonists and kappa receptor agonists may be particularly effective in reducing ethanol self-administration. Therefore, we studied the effect of bremazocine on oral ethanol self-administration in rats using a paradigm [unrestricted free-choice drinking of 10% (v/v) ethanol], previously shown to cause long-term neuroadaptations in the nucleus accumbens and caudate putamen. Bremazocine (0.1 mg/kg, once daily for five consecutive days) reduced ethanol drinking by about 50% during the active period of the animals, whereas the intake of sucrose (3-10% w/v) was affected neither in naive nor in ethanol-experienced rats. This effect of bremazocine appeared not to be secondary to its acute sedative effect or the slight increase in total fluid consumption. Unlike bremazocine, the selective kappa-opioid receptor agonist U50,488H (10 mg/kg, once daily) inhibited ethanol drinking only during the first of 5 treatment days and the opioid receptor antagonist naltrexone (0.3-10 mg/kg, once daily) only caused a modest (about 20%) suppression of ethanol drinking during the first hours after drug injection. Thus, bremazocine appears to be far more potent than the clinically applied drug naltrexone in this respect. Our data further support the role of opioid receptors in ethanol reinforcement and indicate that long-acting mixed-action opioids such as bremazocine may be useful as adjuvants for the clinical management of ethanol addiction.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Sensitivity of magnocellular oxytocin neurones to opioid antagonists in rats treated chronically with intracerebroventricular (i.c.v.) morphine.

The identity of the subtype of opioid receptor mediating morphine dependence in relation to oxytocin neurones was investigated. Virgin female rats were implanted with a subcutaneous osmotic minipump to infuse morphine continuously (up to 50 micrograms/h) into a lateral cerebral ventricle. After 5 days of morphine infusion, rats were anesthetized with urethane, and the electrical activity of electrophysiologically identified supraoptic neurones was recorded extracellularly while opioid antagonists were injected i.v. Putative oxytocin cells were excited following low doses of naloxone HCl: 4/7 cells were excited by 1 microgram/kg, 6/7 cells by 2.5 micrograms/kg, and 11/13 cells by doses of 5-50 micrograms/kg. MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan: an antagonist with much greater affinity for kappa-subtype opioid receptors than naloxone) excited oxytocin cells less potently: none of 9 cells was excited by 10 micrograms/kg MR2266, 2/4 cells were by 25-50 micrograms/kg, 3/9 cells by 100 micrograms/kg and only 4/8 by 200-500 micrograms/kg. At low concentrations naloxone is selective for mu-subtype opioid receptors, hence the morphine dependence of oxytocin neurones is probably via mu-receptors. Naloxone methylbromide (MRZ), a quaternary ammonium derivative of naloxone, excited oxytocin cells in morphine-treated rats, but was at least 10 times less potent than naloxone. Thus part of the morphine-withdrawal excitation of oxytocin neurones may be mediated by mu-receptors outside the blood-brain barrier.

Action Potentials↗
PubMed1982

Potency of three opiate antagonists to reverse the inhibitory activity of dynorphin, enkephalins and opioid-like alkaloids on the guinea pig ileum.

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.

Animals↗
PubMed1985

Mu, but not kappa, opioid agonists induce contractions of the canine small intestine ex vivo.

The proposed kappa opioid receptor agonists ethylketocyclazocine (EK), nalorphine, bremazocine and U-50,488H were evaluated for their ability to produce contractions of isolated, vascularly perfused canine small intestinal segments. Responses to these agonists were compared to those of morphine and phenazocine, a mu benzomorphan. Morphine (0.04-25 micrograms) and phenazocine (0.01-3.0 micrograms) both produced naloxone-reversible contractions, suggesting that the responses were mediated largely by mu opioid receptors. In contrast, the proposed kappa agonists were ineffective in producing intestinal stimulation, with only EK (1-100 micrograms) showing minimal but significant activity at very high doses. We suggest that the effects of EK may be mediated through mu opioid receptors and that kappa receptors appear not to be involved in the contractile response of the dog small intestine to opioids.

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

Comparison of kappa 2-opioid receptors in guinea pig brain and guinea pig ileum membranes.

The presence of kappa-opioid receptor subtypes has been clearly established in guinea pig brain. Using [3H]bremazocine in the presence of reversible blockers of mu, delta and kappa 1 receptors, two additional binding sites can be determined in guinea pig brain membranes. The site with higher affinity for the opioid ligands represents kappa 2, while the other site has low affinity and is poorly characterized. The kappa 2 site has high affinity for ethylketocyclazocine and other benzomorphans, as well as for the dynorphin gene products tested. The dynorphin analogs have no appreciable affinity for the low affinity site, so this site should not be called a kappa receptor. With an appropriate membrane preparation, kappa 2 binding can also be demonstrated in the guinea pig ileum. Binding affinities for selected ligands at kappa 2 in guinea pig ileum membranes are very similar to affinities found in brain membranes.

Analgesics↗
PubMed1993

A comparison of (-)-deoxybenzomorphans devoid of opiate activity with their dextrorotatory phenolic counterparts suggests role of sigma 2 receptors in motor function.

Three novel benzomorphans, (+)-N-benzylnormetazocine, (-)-deoxy-N-benzylnormetazocine, and (-)-deoxypentazocine were tested for their ability to produce circling behavior in rats following intranigral microinjections. Dose studies revealed the following rank order of potency: (-)-deoxypentazocine > (-)-deoxy-N-benzylnormetazocine > (+)-N-benzylnormetazocine. This rank order approximates that for affinities for sigma 2 receptors but not sigma 1 receptors. It is very unlikely that the effects of the (-)-deoxybenzomorphans were mediated by opiate receptors for the following reasons: (1) consistent with the known requirement for the phenolic hydroxyl group for opiate activity, both (-)-deoxy compounds showed very low affinity for opiate receptors; (2) naloxone (4 micrograms) co-administered with (-)-deoxy-N-benzylnormetazocine failed to reduce its efficacy; (3) both (-)-deoxy compounds failed to produce marked analgesic effects in the tail flick test following systemic injections of 20 mg/kg s.c. These finding suggest that sigma 2 receptors mediate the motor effects of sigma ligands in rats.

Animals↗