Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Benzomorphans”

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

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

At least 55 records · Page 3Linked to original sources
PubMed1977

Potential long acting opiate antagonists: preparation, pharmacological activity, and opiate-receptor binding of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans.

A homologous series of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans (hydrogen to octyl inclusive, allyl, and cyclopropylmethyl) was prepared. In contradistinction to the normetazocine, normorphine, and (-)-3-hydroxymorphinan series, the N-pentyl and N-hexyl derivatives do not have the analgesic potency of the parent N-methyl compound; instead, they are narcotic antagonists with a long duration of action. All of the N-substituted 9 alpha-propylbenzomorphans, except for methyl, heptyl, and octyl, have antagonist activity. The receptor binding constants of the N-alkyl compounds are uniformly two- to threefold lower than those of the N-substituted normetazocines.

Analgesics↗
PubMed1987

Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of sigma-type and phencyclidine receptors.

Brain sigma-type receptors and phencyclidine receptors are thought to mediate the psychotomimetic effects of benzomorphans and phencyclidine in humans. Recently, we reported the characterization of a selective sigma receptor ligand, 1,3-di-o-tolyl-guanidine (DTG), that shows negligible crossreactivity with phencyclidine receptors. Here we describe the synthesis and characterization of an isothiocyanate derivative of DTG, di-o-tolyl-guanidine-isothiocyanate (DIGIT). Guinea pig brain membranes treated with nanomolar doses of DIGIT followed by extensive washing exhibit a dose dependent reduction of [3H]DTG and (+)[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)[3H]3-PPP) binding to sigma receptors. Binding of radiolabelled ligands for phencyclidine, mu-opioid, benzodiazepine and dopamine-D2 receptors is not affected by membrane treatment with DIGIT, indicating specificity of the affinity label for sigma-type receptors. Treatment of DIGIT-derivatized membranes with 2 M NaCl does not result in recovery of sigma binding activity, suggesting that DIGIT's interaction with sigma receptors is not of an ionic nature. Equilibrium saturation binding experiments show that the inhibition of [3H]DTG binding to sigma receptors by DIGIT pretreatment of membranes is attributable to an irreversible reduction in the affinity (increase in Kd) of sigma receptors for DTG. The finding that sigma receptors are irreversibly modified by DIGIT whereas phencyclidine receptors are not affected suggests that sigma receptors are physically separate from phencyclidine receptors. The availability of a selective affinity label for the sigma receptor should facilitate the purification of the receptors and the characterization of sigma-type pharmacological effects in vivo and in vitro.

Affinity Labels↗
PubMed1983

Agonist and antagonist properties of some benzomorphans on nociceptive reaction and intestinal transit in rats.

The agonist and antagonist properties of bremazocine, ethylketazocine, Mr 2034 and Mr 2092, benzomorphans with the same pharmacological actions in vitro, were studied in vivo in rats. Overnight fasted animals were tested for nociceptive reaction on a 55 degrees C hot-plate and for the intestinal transit of a charcoal meal fed 5 min earlier. The antagonist activity was assessed by the drugs' ability to prevent morphine-induced constipation. Bremazocine was an agonist on the nociceptive reaction and a pure antagonist on intestinal propulsion; ethylketazocine and Mr 2034 were pure agonists in both tests and Mr 2092 was a mixed agonist-antagonist in the intestinal transit test. Thus the in vivo agonist-antagonist properties of opiates cannot always be predicted from their in vitro characteristics.

Analgesia↗
PubMed1990

Specificity of phencyclidine-like drugs and benzomorphan opiates for two high affinity phencyclidine binding sites in guinea pig brain.

Recently, the presence of two high affinity binding sites for phencyclidine were described in guinea pig brain, with one site coupled to the glutamate excitatory amino acid receptor, specifically activated by N-methyl-D-aspartate (NMDA) (site 1) and the other site associated with the dopamine (DA) reuptake carrier (site 2). Phencyclidine and its analogs, as well as the benzomorphan opiates, are known to interact with binding sites for phencyclidine. In this study, the equilibrium dissociation constants (Kd) of these compounds for the two binding sites for phencyclidine were determined. Phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analog of PCP, were essentially non-selective between the two sites and also were the two drugs of the group observed to have the highest affinity for site 2. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine [(+)MK801] was the most selective agent for site 1, while none of the drugs tested showed selectivity for site 2. In humans, phencyclidine produces psychotomimetic effects, while (+)MK801 has been reported to produce minimal, if any, psychotomimetic effects, at doses sufficient to reduce seizures. These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2.

Analgesics↗
PubMed1985

N-tetrahydrofurfuryl benzomorphans: comparison of a kappa and an agonist/antagonist analgesic.

The N-tetrahydrofurfuryl benzomorphan, MK-2034 is a prototype kappa agonist analgesic. Dehydrogenation and addition of a methyl group into the N-furfuryl side chain (MR-1353) results in a 2-fold decrease in analgesic potency, a 12-fold decrease in affinity for the mu receptor, a 5-fold decrease in affinity for the delta receptor and a 60-fold decrease in affinity for the kappa receptor. Both compounds possess intermediate sodium ratios for 3H-naloxone binding; however, unlike MR-2034, MR-1353 possesses a bell-shaped dose response curve for elevations in striatal dopamine metabolites. These data indicate that MR-1353 is an agonist/antagonist analgesic and suggest that the high kappa affinity of MR-2034 is responsible for the potent analgesia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effects of the benzomorphan kappa-opiate, MR 2266 and its (+) enantiomer MR 2267, on thermonociceptive reactions in different strains of mice.

The effects of the benzomorphan kappa opiate MR 2266 and its dextro enantiomer MR 2267 were assessed on thermonociception in Swiss Webster, C57BL/6, BALB/c and DBA/2 strains of mice. In the hot plate (60 +/- 0.5 degrees C, cut-off time 120 s and tail immersion tests, MR 2266 (10 mg/kg, s.c., 15 min before) decreased, while MR 2267 (10 mg/kg s.c., 15 min before) increased the reaction latencies. In the hot plate test, the sensitivities for the effects of MR 2266 and MR 2267 on jump latency in different strains of mice were as follows: MR 2266; BALB greater than Swiss greater than C57BL greater than DBA and MR 2267; DBA greater than BALB = Swiss greater than C57BL. In the immersion test, for the hyperalgesic response of MR 2266, the rank order of strains was; BALB greater than C57BL and DBA greater than or equal to Swiss while the rank order for the analgesic effect of MR 2267 was; Swiss greater than DBA and BALB. The results indicate the presence of tonic kappa-receptor-mediated regulation of the spinal and supra-spinal thermonociceptive reactions which is stereospecific and strain dependent.

Animals↗
PubMed2004

Kappa-opioid receptors are differentially labeled by arylacetamides and benzomorphans.

Using Chinese Hamster Ovary cell membranes that stably expressed the human kappa-opioid receptor, we investigated the hypothesis that kappa(1)- and kappa(2)-opioid receptors, historically defined by their pharmacological selectivity for either arylacetamides or benzomorphans are, in fact, different affinity states or binding sites on the same kappa-opioid receptors. Receptor binding studies showed that GTP gamma S potently inhibited [3H](5 alpha,7 alpha,8 beta)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro [4.5]dec-8-yl)-benzeneacetamide (U69,593) binding, compared to virtually no inhibition of [3H]bremazocine binding. Saturation binding experiments showed a three-fold decrease in [3H]U69,593 affinity in the presence of GTP gamma S, but GTP gamma S had no effect on [3H]bremazocine affinity. The kappa-opioid receptor antagonist nor-binaltorphimine had a four-fold higher affinity for [3H]U69,593-labeled receptors than for [3H]bremazocine-labeled receptors. Functional selectivity studies, measuring the stimulation of [35S]GTP gamma S agonist-induced binding, showed a significantly higher U69,593-induced G protein-receptor activation in comparison to the stimulation observed with bremazocine. These results suggest that pharmacologically defined 1 kappa-opioid receptor subtypes may be different affinity states of the same receptor.

Acetamides↗
PubMed2003

Migratory hydroamination: a facile enantioselective synthesis of benzomorphans.

We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis.

Amination↗
PubMed1979

Syntheses, analgetic activity, and physical dependence capacity of 5-phenyl-6,7-benzomorphan derivatives.

The synthesis, analgetic activity, and physical dependence capacity of a large number of 5-phenyl-6,7-benzomorphan derivatives are described. Observations made during the Stevens' rearrangement of 1-benzyl-1-methyl-delta 3-piperidinium salt derivatives (V) under various conditions are discussed. The absolute configuration of the 9-demethyl series and the 2'-deoxy series is established by comparison of their ORD and CD spectra with those of 49, whose absolute configuration was previously established by X-ray crystallography. A convenient synthesis of 3H-labeled phenols using 3H3PO4 is described, as well as the preparation of 14C-labeled compounds by conventional methods.

Analgesics, Opioid↗
PubMed1979

N-(2-Cyanoethyl) derivatives of meperidine, ketobemidone, and a potent 6,7-benzomorphan.

The N-(2-cyanoethyl)-9alpha-ethyl-5-methyl-6,7-benzomorphan (1c) is a more potent antinociceptive and has stronger receptor binding affinity than its N-methyl analogue 1b. The N-(2-cyanoethyl)-4-phenylpiperidine compounds 2b and 3b were almost inactive compared to their N-methyl congeners 2a and 3a, respectively. It appears that the pharmacological effect of the N-(2-cyanoethyl) moiety is dependent on the opioid on which it is substituted.

Analgesics↗
PubMed1978

Analgesics and narcotic antagonists in the benzomorphan and 8-oxamorphinan series. 5.

3-Methoxy-8-oxamorphinans 9 have been prepared from the corresponding 5-allyl-9alpha-hydroxy-2'-methoxy-2-methyl-6,7-benzomorphans 7. The former compounds were transformed to the 3-hydroxy-8-oxamorphinans 6, a class of potent analgesics and analgesic-antagonists. In ring C of the morphinan nucleus substitution of 8-CH2 with oxygen enhanced both analgesic and antagonist activities, while replacement of hydrogen with a methyl group at C-14 in these compounds enhanced antagonist activity and decreased analgesic activity. Tetrahydrofuranobenzomorphans 3 and 3-hydroxy-8-oxaisomorphinans 4 displayed lower levels of activity. Structural requirements for antagonist activity are discussed.

Analgesics↗
PubMed1978

Benzomorphans. Structure of a position isomer.

May's benzomorphan synthesis leads not only to the alpha or cis isomer and the beta or trans isomer but also to a position isomer hereinafter called the gamma isomer. The structure and synthesis of this isomer are described. Biological activities of the alpha and gamma isomers are compared.

Animals↗
PubMed1978

Synthesis and analgetic activity of some benzomorphan analogues.

The benzomorphan analogues, 8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-3-benzazepine (1), 8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-2-benzazepine (2), 9-hydroxy-2-methyl-1,2,3,4,5,6-hexahydro-1,5,-methano-2-benzazocine (3), and 10-hydroxy-2-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-2-benzazonine (4), have been synthesized in order to evaluate their analgetic activity. Only slight analgetic activity was found in any of these compounds. The importance of nitrogen to aromatic ring distance for the analgetic-receptor interaction is discussed.

Analgesics↗
PubMed1976

Optical resolution of (+/-)-2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans and their pharmacological properties.

The levo and dextro isomers of 2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans have been prepared. The analgesic potency and physical dependence capacity of the optical isomers and their racemic parents were determined. The 9alpha-propyl levo isomer was analgesically equipotent with morphine; the 9beta-propyl levo isomer was considerably more potent subcutaneously and equipotent orally. None of the optical isomers suppressed the withdrawal syndrome; the 9beta-propyl levo isomer exacerbated the withdrawal syndrome.

Analgesics↗
PubMed1975

Effect of 9-hydroxylation on benzomorphan antagonist activity.

In a benzomorphan bearing an antagonist side chain, introduction on the methano bridge of a hydroxyl oriented away from nitrogen has little effect on antagonist activity whereas a hydroxyl oriented toward nitrogen enhances this activity. Hydroxylation tends to decrease analgesic activity.

Animals↗
PubMed1975

Stereoisomeric 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with non-morphine-like action profiles.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.

Analgesia↗
PubMed2002

Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke.

We have synthesized a series of 6,7-benzomorphan derivatives and determined their ability to bind to voltage-dependent sodium channels. We have also compared the functional consequences of this blockade in vitro and in vivo. The ability of the compounds to displace [(3)H]batrachotoxin from voltage-dependent sodium channels was compared with their ability to inhibit [(3)H]glutamate release in rat brain slices and block convulsions in the maximal electroshock test in mice. We found that the hydroxyl function in the 4'-position is crucial for improving the sodium channel blocking properties. Moreover, the stereochemistry and the topology of the N-linked side chain also influence this interaction. Indeed, the affinity is improved by an aromatic substitution in the side chain. By modifying the N substituent and the substitution pattern of the hydroxyl function, we were able to discover (2R)-[2alpha,3(S),6alpha]-1,2,3,4,5,6-hexahydro-6,11,11-tri-methyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride. This compound was chosen as the best candidate for further pharmacological investigations.

Animals↗