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At least 685 records · Page 38Linked to original sources
PubMed1982

U-50,488, a selective kappa opioid agonist: comparison to other reputed kappa agonists.

1. U-50,488 is a structurally novel, non-mu opioid. In the present experiments it was compared to the reputed kappa opioid agonists, ketazocine, ethylketocyclazocine and bremazocine as regards analgesic cross tolerance to morphine and U-50,488, antagonism of analgesia by naloxone and MR-2266 (in vivo pA2 determination), and narcotic antagonist properties (antagonism of morphine analgesia and precipitation of abstinence in morphine-dependent mice). 2. The analgesic mechanism of bremazocine was similar to that of U-50,488 but the former compound had, in addition, considerable mu-antagonist activity. The analgesic mechanisms of the ketazocines were less selective; both shared both mu and kappa agonist properties. U-50, 488, however, had no such mu agonist or antagonist effects and thus is a more selective kappa agonist. 3. This compound and its congeners may prove useful in the elucidation of the functions of kappa receptors in the central nervous system.

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

Coupling of the cloned rat kappa-opioid receptor to adenylyl cyclase is dependent on receptor expression.

This study describes the coupling of the recombinant rat kappa-opioid receptor expressed in Chinese hamster ovary (CHO) cells to adenylyl cyclase and the effects of receptor density. The binding of [3H]diprenorphine ([3H]DPN) was dose dependent and saturable in membranes prepared from cells of early (p4-7) and late (p14-17) passage after transfection. As passage increased the receptor numbers (Bmax) declined from 231 +/- 24 (early) to 31 +/- 2 fmol/mg protein (late) but the equilibrium dissociation constant (Kd) did not change. Spiradoline dose dependently displaced [3H]DPN from membranes prepared from early and late cells revealing both high (Ki[H]) and low (Ki[L]) affinity binding sites. There were no significant differences in the proportion of these sites (approximately 50% Ki(L):50% Ki[H]), and whilst spiradoline was generally less potent in late cells the differences were small and failed to reach statistical significance. In contrast, spiradoline produced a dose dependent inhibition of forskolin stimulated cAMP formation in whole cells with pIC50 of 8.62 and 8.00 in early compared with late cells. In addition, the maximum inhibition was dramatically reduced from 47 to 22%. Etorphine, (+/-)bremazocine, ICI-204,448 and (+/-)trans-U-50488 methanesulfonate (1 microM), compounds with activity at kappa-receptors, produced a greater inhibition of cAMP formation in early (42.2, 45.8, 50.2 and 50.5%, respectively) than late (12.9, 11.8, 13.5 and 7.8%, respectively) cells, indicating that expression dependent inhibition of cAMP formation was not kappa-agonist specific. Collectively, these data suggest that in CHO cells, kappa-opioid receptor coupling to adenylyl cyclase is dependent on receptor expression levels.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Receptor-mediated activation of G-proteins by kappa opioid agonists in frog (Rana esculenta) brain membranes.

This study delineates the heterotrimeric guanine nucleotide binding regulatory protein (G-protein) types in frog (Rana esculenta) brain membranes and their activation by kappa opioid agonists. Ethylketocyclazocine (EKC), trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)b enzeneacetamide (U-50,488) and bremazocine displayed dose-dependent, norbinaltorphimine-reversible stimulation of guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding in crude membrane preparations. G-proteins were identified by Western-blotting using previously characterized specific antisera that were generated against mammalian G-protein alpha-subunits and beta-subunits. A photoreactive guanosine 5'-triphosphate (GTP) analog, [alpha-32P]GTP azidoanilide ([alpha-32P]AA-GTP) irreversibly labeled four proteins in the molecular weight range of 39-43 kDa. Ethylketocyclazocine and U-50,488 stimulated photolabelling of these proteins among which the 39 kDa band comigrated with the protein specifically labelled with the alpha(i2) antibody and the 40 kDa band was identified as alpha(o1). The other two bands were also stained with the alpha(common) antibody, but were not further identified. These results suggest that the endogenously expressed kappa opioid receptors that are present in frog brain interact with multiple G-proteins in situ. Furthermore, the structure of most G-proteins seems to be well preserved during phylogenesis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Effects of mu and kappa opioid receptor antagonists on glucoprivic induction of Fos immunoreactivity in the rat preoptic area and hypothalamus.

Interoreceptors in the central nervous system elicit compensatory behavioral and physiological responses to cellular glucopenia. Antagonism of mu and kappa opioid receptors attenuates glucoprivic hyperphagia, findings that implicate these peptidergic receptors in the central processing of metabolic regulatory signals. Several hypothalamic structures of critical importance for the regulation of energy balance exhibit one or both of these receptors. The following studies investigated the role of these opioid receptors in glucoprivic induction of immediate-early gene expression in these brain sites. Male rats were pretreated with beta-funaltrexamine (mu antagonist), Mr-1452 MS (kappa antagonist), or vehicle prior to intraperitoneal injection of the glucose antimetabolite, 2-deoxy-D-glucose (2DG), then sacrificed by transcardial perfusion 2 h later. Nuclear immunolabeling for the transcription factor, Fos, was observed in several preoptic and hypothalamic sites following 2DG administration. Rats pretreated with the mu antagonist exhibited significantly fewer Fos-positive neurons in the medial preoptic area and dorsomedial hypothalamic nucleus in response to 2DG, compared to vehicle-pretreated controls. Blockade of kappa receptors diminished 2DG and induced Fos staining in the paraventricular and supraoptic nuclei. Numbers of Fos-positive cells in the arcuate nucleus and ventrolateral hypothalamic area were not altered by either antagonist. The present data implicate mu and kappa opioid receptors in neural mechanisms underlying glucoprivic induction of the Fos stimulus-transcription pathway by local neurons in discrete hypothalamic sites.

Animals↗
PubMed1997

Comparison of the effects of a series of kappa-opioid receptor agonists upon sodium channel function in rat brain miniprisms.

The blockade of veratrine-stimulated phosphoinositide breakdown in rat cerebral cortical miniprisms has been used as a model of drug action on voltage-dependent sodium channels. The kappa-opioid agonists bremazocine, (+/-)- and (+)-trans-U-50488, U-62066 (spiradoline) and U-69593 inhibited the response to veratrine with IC50 values of 35, 13, 15, 9, and > 100 microM, respectively. Bremazocine, at concentrations inhibiting the response to veratrine, did not inhibit the phosphoinositide breakdown response to the sodium ionophore monensin, indicating the specificity of the assay for sodium channels. The inhibitory actions of bremazocine upon veratrine-stimulated phosphoinositide breakdown were not antagonised by naloxone. This study thus confirms previous data suggesting that the kappa-opioid receptor agonists can affect Na(+)-channel function in a manner unrelated to their actions at kappa-opioid receptors. However, for the compounds tested, such effects are only found at rather high concentrations of the compounds.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Opioid-dopamine interaction in planaria: a behavioral study.

The behavioral response of planaria to the exposure to selective opioid agonists was studied. The mu agonist [d-ala2, N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO) and the 6 agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) failed to alter motor activity at all doses tested. Low doses of the selective kappa agonist (+/-)-trans-U-50-trans-3,4-dichloro-N-methyl-N[2-(1-pyrrodinyl)-cyclohexyl]benzene acetamide methasulphonate (U50, 488) and bremazocine-HCl increased motor activity leading to C-like position (CLP) and screw-like hyperkinesia (SLH). These changes were identical to those seen previously with the exposure to D2 or D1 dopamine receptor agonists, respectively. Higher doses of kappa agonists produced the enhancement of CLP and SLH together with robust snake-like movements (SLM). This latter response, that was typical of stimulation of kappa opioid receptors, was blocked by co-exposure to naloxone or the selective kappa antagonist Nor-binaltorphimine (Nor-BNI). Finally, co-exposure to sulpiride or SH-23390 respectively blocked the CLP or SLH response produced by U50,488 or bremazocine. Our data indicate the presence of kappa opioid receptors in planaria and suggest the functional interaction between the opioid and dopamine system in this simple animal model.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

The conserved cysteine 7.38 residue is differentially accessible in the binding-site crevices of the mu, delta, and kappa opioid receptors.

Binding pockets of the opioid receptors are presumably formed among the transmembrane domains (TMDs) and are accessible from the extracellular medium. In this study, we determined the sensitivity of binding of [(3)H]diprenorphine, an antagonist, to mu, delta, and kappa opioid receptors to charged methanethiosulfonate (MTS) derivatives and identified the cysteine residues within the TMDs that conferred the sensitivity. Incubation of the mu opioid receptor expressed in HEK293 cells with MTS ethylammonium (MTSEA), MTS ethyltrimethylammonium (MTSET), or MTS ethylsulfonate (MTSES) inhibited [(3)H]diprenorphine binding with the potency order of MTSEA > MTSET > MTSES. Pretreatment of mu, delta, and kappa opioid receptors with MTSEA dose-dependently inhibited [(3)H]diprenorphine binding with MTSEA sensitivity in the order of kappa > mu >> delta. The effects of MTSEA occurred rapidly, reaching the maximal inhibition in 10 min. (-)-Naloxone, but not (+)-naloxone, prevented the MTSEA effect, demonstrating that the reaction occurs within or in the vicinity of the binding pockets. Each cysteine residue in the TMDs of the three receptors was mutated singly, and the effects of MTSEA treatment were examined. The mutants had similar affinities for [(3)H]diprenorphine, and C7. 38(321)S, C7.38(303)S, and C7.38(315)S mutations rendered mu, delta, and kappa opioid receptors less sensitive to the effect of MTSEA, respectively. These results indicate that the conserved Cys7.38 is differentially accessible in the binding-site crevice of these receptors. The second extracellular loop of the kappa receptor, which contains several acidic residues, appears to play a role, albeit small, in its higher sensitivity to MTSEA, whereas the negative charge of Glu6.58(297) did not. To the best of our knowledge, this is the first report to show that a conserved residue among highly homologous G protein-coupled receptors is differentially accessible in the binding-site crevice. In addition, this represents the first successful generation of MTSEA-insensitive mutants of mu, delta, and kappa opioid receptors, which will allow determination of residues accessible in the binding-site crevices of these receptors by the substituted cysteine accessibility method.

Amino Acid Sequence↗
PubMed1981

Preparation and analgesic properties of amino acid derivatives of (-)-5,9 alpha-diethyl-2'-hydroxybenzomorphan.

The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,9 alpha-diethyl-2'-hydroxybenzomorphan was prepared and evaluated for analgesic activity. In vitro activities were found to vary greatly, depending on the nature of the amino acid used. The N-arginyl derivative was found to be equipotent to (-)-5,9 alpha-diethyl-2'hydroxybenzomorphan and also to methionine-enkephaline in the naloxone binding assay.

Amino Acids↗
PubMed1990

Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6 alpha- and 6 beta-naltrexol.

Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assay against [3H]bremazocine and more active against [3H]DAGO, indicating mu-subtype selectivity, but only ether 12 showed significant irreversible activity. We conclude that small structural changes, made in very closely related electrophilic opioids, lead to changes in receptor binding. All four compounds were long-acting antagonists to morphine in mice, with ester 10 being approximately equipotent with naltrexone.

Animals↗
PubMed1990

Probes for narcotic receptor mediated phenomena. 17. Synthesis and evaluation of a series of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet amide (U50,488) related isothiocyanate derivatives as opioid receptor affinity ligands.

A series of U50,488 related isothiocyanates was synthesized from enantiomerically pure (S,S)-(+)-trans-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-7] and (R,R)-(-)-trans-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-7]. DCC coupling of (+)- and (-)-7 with nitrophenylacetic acids followed by catalytic hydrogenation and treatment with thiophosgene afforded a series of six isomeric aryl isothiocyanate analogues of U50,488. Similarly, DCC coupling of (+)- and (-)-7 with (+)- and (-)-N-t-Boc-protected phenylglycines afforded four isomeric alkyl isothiocyanates. Evaluation of the isothiocyanates for their capacity to produce wash-resistant inhibition of mu, delta, and kappa sites in vitro was performed using rat and guinea pig brain membranes. None of the compounds was able to irreversibly inhibit binding of [3H]bremazocine to guinea pig and rat brain membranes (depleted of functional mu and delta receptors by pretreatment with acylating agents BIT and FIT). However, (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1] was able to specifically and irreversibly inhibit kappa receptors labeled by [3H]-U69,593: Incubation of rat brain membranes for 60 min at 25 degrees C with 1 microM of (-)-1 resulted in a wash-resistant reduction of the binding to 11.2 +/- 2.5% of the control. Binding analysis revealed the wash-resistant reduction in [3H]-U69,593 binding by (-)-1 to be through an increase in the Kd without effect on the Bmax. (-)-1 failed to effect mu or delta binding in rat or guinea pig brain under the same conditions. The enantiomer of (-)-1, (1R,2R)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(+)-1], failed to affect kappa receptors labeled by [3H]-U69,593 under the same conditions as for (-)-1. (1S,2S)-trans-3-Isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-2] inhibited to 49.6 +/- 5.1% of the control, in a wash-resistant manner, kappa receptors labeled by [3H]-U69,593. However, (-)-2 was not as selective as (-)-1 since it also reduced [3H]DADLE (delta) binding to 82.4 +/- 8.0% of the control value. (1S,2S)-trans-4-Isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide [(-)-3] exhibited selective wash-resistant inhibition of delta receptors labeled by [3H]DADLE resulting in a reduction in binding to 42.9 +/- 4.2% of control.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Synthesis and evaluation of N-substituted cis-N-methyl-2-(1-pyrrolidinyl)cyclohexylamines as high affinity sigma receptor ligands. Identification of a new class of highly potent and selective sigma receptor probes.

Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide] were recently reported to be potent sigma receptor ligands. In order to determine whether efficacy for the sigma receptor could be improved, a series of compounds related to the benzeneacetamides, N-substituted cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (+/-)-, 1S,2R-(+)-, and 1R,2S-(-)-cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of sigma ([3H](+)-3-PPP), kappa ([3H]bremazocine and [3H]U69,593), dopamine-d2 ([3H](-)-sulpiride), and phencyclidine (PCP) ([3H]TCP) receptor binding in guinea pig brain revealed a number of highly potent and selective sigma receptor ligands. Notably, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl) acetamide [(-)-29] (Ki = 8.66 +/- 0.35 nM), (+/-)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide [(+/-)-17] (Ki = 11 +/- 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine [(-)-44] (Ki = 1.3 +/- 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine. [(+)-44] (Ki = 6 +/- 3 nM) exhibited very high affinity at sigma receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [( 3H]-(+)-3-PPP). These compounds showed insignificant affinity for kappa, dopamine, or PCP receptors, making them valuable tools for the study of sigma receptors. Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (-)-29. Several other compounds showed equivalent selectivity but displayed lower sigma receptor affinity.

Animals↗
PubMed1980

Synthesis and biological activity of fluoroalkylamine derivatives of narcotic analgesics.

N-Ethyl-, N-(2-fluoroethyl)-, N-(2,2-difluoroethyl)-, and N-(2,2,2-trifluoroethyl)-substituted normeperidine (1b-e) and normetazocine (2b-e) derivatives were prepared. The analgesic activities of the compounds were determined in mice. Opiate receptor binding studies, in the presence and absence of sodium ion, were carried out. The antagonist activities of normetazocine derivatives were studied in monkeys. These were further examined in the isolated guinea pig ileum for relative agonist activity. The pKa values were measured; in vivo agonist acitivty was lost with weakly basic derivatives. For the normetazocine derivatives, opiate receptor binding data were consistent with guinea pig ileum agonist potency and mouse vas deferens antagonist potency but not with in vivo data. Opiate receptor binding was reduced for the less basic normetazocine derivatives. In the normeperidine series, there was no apparent direct relationship between pKa and opiate receptor binding. However, a relationship involving the hydrophobic character of the N-substituent is discussed. The N-(2-fluoroethyl) derivatives in both series were found to cause convulsions in rats at doses of 40-45 mg/kg ip. Elevated serum citrate levels were found in these rats, implicating in vivo oxidative deamination of the N-(fluoroalkyl) substituent to fluoroacetate.

Analgesics, Opioid↗
PubMed1979

Optical resolution of some homobenzomorphan derivatives and their pharmacological properties.

Racemic 1,4-dimethyl- (1), 1,4,12 alpha-trimethyl- (2), and 1,4,12 beta-trimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine (3) have been optically resolved. The analgesic potency and physical-dependence capacity of the optical isomers and their racemic parents were determined. The levo isomers of compounds 2 and 3 were analgesically much more potent than the dextro isomers and were equipotent with morphine. Optical resolution gave no effect on the activity of compound 1. None of the optical isomers and the racemates suppressed the morphine-withdrawal syndrome in the monkey.

Analgesics↗