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PubMed1993

Antagonism of a (+)N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs.

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at sigma- and phencyclidine (PCP) receptors. Although the low-affinity sigma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands--(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)--antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither establish a role for sigma involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that sigma-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Acute sensitization to opioid antagonists.

Acute morphine pretreatment sensitizes rats to the response rate-decreasing effects of opioid antagonists naloxone and naltrexone. The effect appears to be mu-opioid receptor specific, as pretreatment with non-mu-selective opioid agonists results in less pronounced sensitization. In the present study, food-deprived rats were trained to respond for food reinforcement on a FI 3-min schedule (9.5 min) with multiple trials. Doses of opioid antagonists were administered cumulatively before each trial of a session following 4-h pretreatment with either vehicle or morphine (3.0 mg/kg). Morphine pretreatment sensitized rats to naltrexone, lowering its ED50 from 20 to 0.03 mg/kg. It also sensitized rats to naloxone and to diprenorphine, another pure antagonist. Morphine-induced sensitization was stereoselective among the optical isomers of the benzomorphans, cyclazocine, pentazocine, and N-allylnormetzocine. In addition, acute morphine pretreatment resulted in sensitization to the mixed agonist/antagonist nalorphine, but not to buprenorphine or nalbuphine. The results extend previous findings concerning the importance of the mu-opioid receptor in the development of sensitization to opioid antagonists.

Animals↗
PubMed1984

Hamster vas deferens contains delta-opioid receptors.

Electrical field stimulation of the hamster, isolated vas deferens produces regular contractions that are unaffected by opioid-receptor agonists which are selective for the mu- or kappa-receptor types. However, agonists which show a selectivity for the delta-opioid receptor produce dose-related inhibitions of the stimulation-evoked contractions. Response of delta-opioid receptor agonists are antagonized in a competitive fashion by the selective delta-receptor antagonist ICI 174864, and also by naloxone. The "kappa-opioid-agonist" benzomorphans, bremazocine and ethylketocyclazocine are antagonists in the hamster vas deferens; bremazocine is particularly potent in this regard. In conclusion, the hamster, isolated vas deferens may contain only delta-opioid receptors and provides a simple and specific test for the assay of activity at the delta-opioid receptor.

Animals↗
PubMed1984

Opioid binding sites in different levels of rat spinal cord.

Opioid receptor binding sites were analyzed in various segments of rat spinal cord. Mu and delta types were labelled with [3H]-DHM or [3H]-DAGO and [3H]-DADLE or [3H]-DSLET respectively. Kappa 1 (kappa) and kappa 2 (benzomorphan) binding sites were individually detected by the overall labeling of opioid binding sites with [3H]-etorphine followed by the elimination of binding to particular sites by the use of appropriate selective unlabelled ligands. Whereas lumbo sacral region contained mainly the kappa 2 site, thoracic membranes had a proportion of approximately 20% mu, 20% kappa 1 and 60% kappa 2 and cervical region contained much less kappa 2 sites (25% mu, 20% delta, 28% kappa 1 and 32% kappa 2).

Animals↗
PubMed1989

The effect of prototypic sigma ligands on the binding of [3H]dextromethorphan to guinea pig brain.

We studied the effects of several prototypic sigma site ligands on the binding of [3H]dextromethorphan ([3H]DM) to guinea pig brain. Haloperidol, 3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine [+)-3-PPP) and (+)-N-allyl-N-normetazocine [+)-NANM or (+)-SKF10,047), which are potent sigma site ligands, showed high affinity for [3H]DM binding sites. The rank order of potency of sigma ligands, as indicated by the Ki values for the high-affinity sites is: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than (+)-SKF10,047 greater than (-)-butaclamol much greater than (+)-butaclamol greater than (-)-SKF10,047. This rank order of potency is similar to that for the sites labeled with [3H](+)-3-PPP and [3H](+)-SKF10,047. The (+)-isomers of several benzomorphans displayed higher affinity than the (-)-isomers. (-)-Butaclamol competed against [3H]DM binding more effectively than the (+)-isomer, displaying the same stereospecificity shown for sigma sites. The findings reported here demonstrate that there are previously unrecognized similarities between DM and sigma sites. It is evident that further exploration of the DM, sigma and phencyclidine (PCP) sites will be necessary to establish the physiological role and therapeutic potential of these sites.

Animals↗
PubMed1991

The human sigma site, which resembles that in NCB20 cells, may correspond to a low-affinity site in guinea pig brain.

1,3-di(2-[5-3H]tolyl)Guanidine ([3H]DTG) was found to bind to a single saturable population of binding sites in human cerebral cortex and NCB20 cells, a second low-affinity site was apparent in guinea pig brain. Displacement studies were performed to determine the pharmacology of the [3H]DTG binding site in these 3 membrane preparations. In human cortical tissue and NCB20 cell membranes the (+)-stereoisomers of benzomorphans displaced binding with Hill coefficients close to one, displayed similar affinity and did not give the biphasic displacement curve characteristic of guinea pig membranes. The pIC50 of the low-affinity component of the sigma binding site in guinea pig brain correlates best with the affinity of drugs for the binding site in human cortex.

Animals↗
PubMed1985

Stereospecific opiate binding in living human polymorphonuclear leucocytes.

Living human polymorphonuclear leucocytes were incubated with various opiate agonists and antagonists in radioreceptor assays. Binding of the opiate antagonists 3H-naloxone and 3H-diprenorphine and of the benzomorphan 3H-ethylketocyclazocine was found at 4 degrees C and at 37 degrees C, 3H-naloxone binding was stereospecific. Binding of the opiate agonist 3H-dihydromorphine was present at 37 degrees C but not at 4 degrees C and had a different time course as compared to the antagonists. At both temperatures no specific binding of the proteolytic stable analogue 3H-D-Ala-D-Leu-enkephalin was found. Autoradiography showed an unspecific accumulation of 3H-naloxone inside the cells and a specific localization of grains at the cell membrane.

Analgesics, Opioid↗
PubMed1986

Kappa opioid receptors in human lumbo-sacral spinal cord.

[3H]Etorphine and [3H]ethylketocyclazocine bind with high affinity (Kd between 0.25-2.0 nM) to a single class of sites in human lumbo-sacral spinal cord. Other ligands such as [3H]morphine, [3H]dihydromorphine and [3H]D-Ala2, D-Leu5-enkephalin (DADLE) did not bind to significant number of sites under our incubation conditions. Ligand selectivity pattern strongly suggests that [3H]etorphine labels kappa opioid binding sites in the human lumbo-sacral spinal cord since benzomorphans and oripavines are much more potent than mu and delta agonists. Furthermore, [3H]etorphine and [3H]ethylketocyclazocine binding is sensitive to high concentrations of DADLE suggesting that these sites are of the kappa 2 sub-type. Finally, the visualization of these sites by receptor autoradiography demonstrates that they are mainly concentrated in lamina II and III of the dorsal horn. Moderate densities of sites are present around the central canal. Thus, it is possible that kappa opioid binding sites could be involved in the control of sensory and autonomic functions in the human lumbo-sacral spinal cord.

Adult↗
PubMed1986

A behavioral role for enkephalins in regulating locomotor activity in the insect Leucophaea maderae: evidence for high affinity kappa-like opioid binding sites.

D'-Ala-2 met-5-enkephalinamide application to the cerebral ganglia of Leucophaea maderae results in a decrease in locomotor activity. The opiate antagonist, naloxone, can block this effect as well as the depressant effect of morphine on locomotor activity. D-Ala-2,leu-5-enkephalinamide and dynorphin enhance locomotor activity following their topical application to the cerebral ganglia. This effect also can be antagonized by concomitant naloxone treatment. Benzomorphans were the most potent ligands tested in their ability to displace [3H]D'-ala-2,met-5-enkephalinamide whereas mu and delta ligands were by comparison less potent. These results suggest the presence of kappa-like opioid receptors in Leucophaea cerebral ganglia. The kappa ligands also are potent in enhancing locomotor activity in addition to being weakly antagonized by naloxone. Again, these results indicate the presence of multiple-opiate receptor types in invertebrates.

Animals↗
PubMed1995

Discriminative stimulus properties of dextromethorphan in rats.

Male Sprague-Dawley rats were trained to discriminate dextromethorphan (DM, 30 mg/kg, ip) from saline using a standard two-lever, fixed ratio 10, food reinforcement procedure. The DM-saline discrimination was acquired, and a range of doses of DM produced a dose-related generalization to the DM-lever choice. Stimulus generalization tests were conducted with dextrorphan, an active metabolite of DM, and with drugs selected from different pharmacological families. Dextrorphan induced a full generalization to DM, but only at a dose higher than the DM training dose. Morphine, a mu opiate receptors agonist, and U 50488, a kappa opiate receptors agonist, failed to substitute for DM. Cyclazocine, a benzomorphan derivative, with high affinity for sigma receptors, was able to produce a complete generalization to DM, without a change in the number of rats responding. Dizocilpine (MK 801), a phencyclidine-like drug, produced a complete generalization, but only at a dose that markedly reduced the number of rats responding. Carbetapentane and caramiphen, antitussive drugs with high affinity for the 'specific DM receptors', failed to substitute for DM. These results show that the discriminative stimulus of DM, did not result primarily from its metabolism to dextrorphan; and the discriminative stimulus properties of DM appear to more closely resemble those of cyclazocine than those of the other drugs tested. This suggests a role of sigma receptors in the mediation of the DM stimulus. These experimental data are discussed with reference to the cyclazocine-like subjective effects produced in man by large doses of DM.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Characterization of the binding of [3H](+)-pentazocine to sigma recognition sites in guinea pig brain.

The selective sigma compound (+)-pentazocine was radiolabeled and its binding characteristics in guinea pig brain membranes were investigated. [3H](+)-Pentazocine bound to a single high-affinity site with a KD of 2.9 nM and a Bmax of 1998 fmol/mg protein. Saturation was achieved at a ligand concentration of 15 nM. Maximal specific binding was observed at 37 degrees C and was greater than 90% of total binding. Equilibrium was reached by 120 min and dissociation was complete by 420 min, with a t1/2 of 121 min. Li+, Ca2+ and Mg2+ inhibited binding at high concentrations, and binding was insensitive to adenyl and guanyl nucleotides. Stereoselectivity was observed for the inhibition of binding by benzomorphans, 3-(3-hydroxyphenyl)-N-propylpiperidine and butaclamol, and the (+) enantiomers and alpha diastereomers of pentazocine and cyclazocine were more potent than their corresponding (-) enantiomers and beta diastereomers. The rank order of potency for the sigma reference agents to displace [3H](+)-pentazocine binding was similar to that reported using the [3H]sigma ligands dextromethorphan, 1,3-di(2-tolyl)guanidine and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine. Haloperidol, (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-propylpiperidine and rimcazole were competitive inhibitors of binding to the [3H](+)-pentazocine-defined sigma recognition site, suggesting that these different structural classes of compounds all bind to a single molecular entity.

Animals↗
PubMed2004

A novel soluble protein factor with non-opioid dynorphin A-binding activity.

A novel soluble non-opioid dynorphin A-binding factor (DABF) was identified and characterized in neuronal cell lines, rat spinal cord, and brain. DABF binds dynorphin A(1-17), dynorphin A(2-17), and the 32 amino acid prodynorphin fragment big dynorphin consisting of dynorphin A and B, but not other opioid and non-opioid peptides, opiates, and benzomorphans. The IC50 for dynorphin A(1-17), dynorphin A(2-17), and big dynorphin is in the 5-10 nM range. Using dynorphin A and big dynorphin fragments a binding epitope was mapped to dynorphin A(6-13). DABF has a molecular mass of about 70 kDa. SH-groups are apparently involved in the binding of dynorphin A since p-hydroxy-mercuribenzoic acid inhibited this process. Upon interaction with DABF dynorphin A was converted into Leu-enkephalin, which remained bound to the protein. These data suggest that DABF functions as an oligopeptidase that forms stable and specific complexes with dynorphin A. The presence of DABF in brain structures and other tissues with low level of prodynorphin expression suggests that DABF as an oligopeptidase may degrade other peptides. Dynorphin A at the sites of its release in the CNS may attenuate this degradation as a competitor when it specifically binds to the enzyme.

Animals↗
PubMed1997

Presence and characterization of nociceptin (orphanin FQ) receptor binding in adult rat and human fetal hypothalamus.

High affinity and saturable nociceptin (orphanin FQ) receptors were detected and characterized in adult rat and human fetal hypothalamic membranes, utilizing [125I]Tyr12-nociceptin as ligand. Nociceptin bound with picomolar affinity, dynorphin A with nanomolar affinity, naloxone and dynorphan A(1-8) with micromolar while des-Tyr1-dynorphin (dynorphin A(2-17)), several other opioids, morphine and benzomorphans failed to compete for binding at 1-10 microM. Gpp(NH)p together with sodium ion markedly decreased binding, consistent with involvement of a G protein-linked receptor.

Animals↗
PubMed1997

Presence of nociceptin (orphanin FQ) receptors in rat retina: comparison with receptors in striatum.

Nociceptin (orphanin FQ), a heptadecapeptide with some sequence homology to dynorphin A, has been proposed as an endogenous ligand for a previously cloned orphan receptor with significant homology to opioid receptors. Utilizing [(125)I][Tyr14]nociceptin as ligand, saturable and high affinity nociceptin binding sites were detected and characterized in rat retina and striatum. For retina, Bmax = 44.0 +/- 4.5 fmol/mg and Kd = 32.4 +/- 2.7 pM; for striatum, Bmax = 51.6 +/- 7.7 fmol/mg and Kd = 98.6 +/- 11.3 pM. In competition studies, nociceptin bound with picomolar affinity, dynorphin A with nanomolar affinity, naloxone and dynorphan A-(1-8) with micromolar affinity, while [des-Tyr1]dynorphin (dynorphin A-(2-17)), several other opioids, morphine and benzomorphans failed to compete for binding at 1-10 microM. Gpp(NH)p plus NaCl markedly decreased binding, consistent with involvement of a G protein-linked receptor. It is concluded that rat retina contains nociceptin receptors similar in concentration to those present in striatum. Properties of both the retinal and the striatal receptors are similar to those previously found for rat hypothalamus.

Animals↗
PubMed1999

Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew).

The anti-emetic mechanism of action of fentanyl to inhibit nicotine (5 mg/kg, s.c.)-induced emesis was investigated in Suncus murinus. The anti-emetic action of fentanyl (40 microg/kg, s.c.) was antagonised by the opioid receptor antagonists naltrexone (1 mg/kg, s.c.), naloxone (1 mg/kg, s.c.), M8008 (16S-methylcyprenorphine; 1 mg/kg, s.c.) and MR 2266 (5,9-diethyl-2-(3-furylmethyl)2'-hydroxy-7,7-benzomorphan; 1 mg/kg) but not by naloxone methylbromide (1 mg/kg, s.c.), naloxone methyliodide (1 mg/kg, s.c.), naltrindole (1 mg/kg, s.c.), DIPPA (2-(3,4-dichlorophenyl)-N-methyl-N-[1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)-ethyl]acetamide; 3 mg/kg, i.p.) or naloxonazine (35 mg/kg, i.p.). This indicates an involvement of mu2-opioid receptors within the brain to mediate the anti-emetic effect of fentanyl. In other studies, naloxone 10-60 mg/kg, s.c. induced dose-related emesis but naltrexone was only emetic at 60 mg/kg, s.c. and naloxone methylbromide failed to induce emesis at doses up to 60 mg/kg, s.c. The emesis induced by a high dose of naloxone 60 mg/kg, s.c. was antagonized by CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; 3-30 mg/kg, i.p.), 8-OH-DPAT, ((+/-)-8-hydroxy-dipropylaminotetralin; 0.003-0.3 mg/kg, s.c.), buspirone (3 mg/kg, s.c.) and fluphenazine (1-3 mg/kg, i.p.) but not by naltrexone (1-30 mg/kg, s.c.), metoclopramide (0.3-3 mg/kg, i.p.), sulpiride (0.3-3 mg/kg, i.p.), domperidone (0.1-3 mg/kg, i.p.), ondansetron (0.3-3 mg/kg, i.p.), granisetron (0.3-3 mg/kg, i.p.), scopolamine (0.3-3 mg/kg, i.p.) or promethazine (0.3-3 mg/kg, i.p.). The data is discussed in relation to opioid receptor mechanisms moderating emesis and the identification of potential sites of drug action available to inhibit the emetic reflex.

Animals↗
PubMedDate not supplied

Specific kappa opioid receptor agonists.

The results of studies on the design of a heterocyclic scaffold for the dynorphin A pharmacophore and on structure-affinity relationships in the MPCB/CCB series are described. The representative ligands provide insights to binding modes of benzomorphan derivatives to the kappa opioid receptor.

Analgesics, Opioid↗
PubMed1984

Structural influences on the amperometric detection of opiates in high-performance liquid chromatography.

The oxidation reactions of a series of opiates occurring at a glassy-carbon electrode in amperometric high-performance liquid chromatographic detection has been investigated. A structure-reactivity correlation has been drawn for morphone, morphinan and benzomorphan derivatives. Polarography and hydrodynamic voltammography were used to show the importance of phenolic groups to this reaction. Acyl substitution on the phenol did not prevent amperometric detection.

Chemical Phenomena↗
PubMed2001

Cocaine affects the dynamics of cytoskeletal proteins via sigma(1) receptors.

Cytoskeletal proteins are important in protein trafficking, membrane protein clustering, dendrite growth and the morphological maintenance of neurons. Sigma(1) receptors are unique endoplasmic reticular (ER) proteins that bind (+)benzomorphans, neurosteroids and psychotropic drugs such as cocaine. Cocaine, via sigma(1) receptors, can cause the dissociation of a cytoskeletal adaptor protein ankyrin from inositol (1,4,5)-trisphosphate [Ins(1,4,5)P(3)] receptors on the ER as a sigma(1)-receptor-ankyrin complex, which then translocates to the plasma membrane and nucleus. The dissociation of sigma(1)-receptor-ankyrin from Ins(1,4,5)P(3) receptors also increases the intracellular Ca(2+) concentration [[Ca(2+)](i)], which affects the activity of cytoskeletal proteins. Furthermore, cocaine might increase [Ca(2+)](i) via phospholipase C (PLC)-linked dopamine D1 receptors. We hypothesize that cocaine might cause life-long changes in neurons via cytoskeletal proteins by interacting with both D1 receptors and sigma(1) receptors.

Animals↗