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At least 19 recordsLinked to original sources
PubMed1992

Replenishment of brain adenosine triphosphate content by morphinan-type N-methyl-D-asparatate receptor antagonists, dextrorphan and dextromethorphan through the activation of adenylate kinase.

The in vitro effects of four N-methyl-D-aspartate (NMDA) receptor antagonists, dextrorphan, (DX, CAS 125-73-5), dextromethorphan, (DM, CAS 125-71-3), dizocilpine (CAS 77086-21-6) and (+/-) 2-amino-7-phosphonoheptanoate (AP-7, CAS 85797-13-3) on rat brain adenylate kinase (AK) have been studied. DM was the most active of the four compounds in increasing rat brain AK activity. DX was slightly less active than DM, while the most potent NMDA antagonist, dizocilpine was somewhat weaker than the above two morphinan analogs (DX and DM). For AP-7, the AK activity was unchanged. The results may indicate that a causal relation cannot be made between the activation of the AK by these compounds and their ability to act as NMDA antagonists. When DX was added, the Km and Vmax values of the enzyme for ADP as a substrate decreased and increased, respectively, possibly reflecting an affinity change for the enzyme-substrate interaction by DX. The observed increase in the AK activity by the morphinan-type NMDA antagonists in vitro might result in their preserving effects on cerebral neuron integrity under the conditions where cerebral energy metabolism is disturbed. This assumption was at least partly confirmed in in vivo tests in which DX, unlike dizocilpine, increased ATP content of the brain in mice under the influence of hypoxia exerted by i.v. injection of KCN.

2-Amino-5-phosphonovalerate↗
PubMed1992

Inhibitory influence of morphinans on ictal and interictal EEG changes induced by cortical application of penicillin in rabbits: a comparative study with NMDA antagonists and pentobarbitone.

The effects of dextrorphan (DX) and dextromethorphan (DM) were tested using the electroencephalogram (EEG) and behavioral effects induced by topical cortical application of penicillin in rabbits. For comparison, the influence of the NMDA antagonists, dizocilpine (MK 801) and 3-((+-(-)2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP), and of pentobarbitone was investigated. Intracortical injection of 500 IU of penicillin produced an EEG spiking followed by a repeated generalization of the electrical and behavioral symptoms. Within a few minutes, DX (5-15 mg/kg, IV) or pentobarbitone (5-10 mg/kg, IV) reduced dose dependently and significantly (p less than 0.01) the interictal and ictal EEG and behavioral effects elicited by cortical injection of 500 IU of penicillin. Higher doses of pentobarbitone (20 mg/kg, IV) but not of DX (20 mg/kg, IV) completely blocked the ictal behavioral and EEG effects elicited by cortical injection of 500 IU of penicillin. Within a few minutes, MK 801 (0.1-0.2 mg/kg, IV) or CPP (10-20 mg/kg, IV) reduced dose dependently and significantly (p less than 0.01) the ictal EEG and behavioral effects elicited by cortical injection of 500 IU of penicillin, while they did not affect the penicillin-induced interictal EEG changes. Higher doses of MK 801 (0.3 mg/kg, IV) completely blocked the ictal behavioral and EEG effects elicited by cortical injection of 500 IU of penicillin. Within a few minutes, DM (10-20 mg/kg, IV) blocked the behavioral effects, but failed to affect either the interictal or the ictal EEG effects induced by cortical injection of 500 IU of penicillin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone.

(+)-Naloxone was prepared in 26% overall yield in eight steps from (+)-7-bromodihydrocodeinone dimethyl ketal by a synthesis which excluded enantiomeric contamination. (+)-Naloxone was examined in three assay systems and found to have no more than 1/1000(-1)/10 000th the activity of (-)-naloxone; it can, thus, serve to test the stereospecificity of the biochemical and pharmacological actions of (-)-naloxone.

Adenylyl Cyclases↗
PubMed1977

Alkaloids of Ocotea brachybotra.

Aporphine, proaporphine and morphinane alkaloids were isolated from the leaves of a Brazilian Lauracea, Ocotea brachybotra (Meiss.) Mez. The known alkaloids were identified through their physico-chemical properties as: (I) (+/-)-glaziovine, (II) dicentrine, (III) ocopodine, (IV) cassynthicine, (V) predicentrine, (VI) leucoxine, (IX) sinacutine and (X) pallidine. The structure of (VI) leucoxine was confirmed by a detailed analysis of the N.M.R. spectra recorded in various conditions. New morphinane alkaloids, (XI) ocobotrine and (XII) 14-espisinomenine, having the unusual B/C-trans configuration were also isolated. Their structures were determined using spectroscopic methods and chemical correlations.

Alkaloids↗
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

Double-blind comparison of butorphanol tartrate and meperidine hydrochloride in balanced anaesthesia.

Butorphanol tartrate, a synthetic morphinan which has analgesic agonist and antagonist properties, was compared with meperidine for balanced anaesthesia. The two agents were found to be comparable in efficacy, maintenance of cardiovascular stability, and incidence of side-effects. Butorphanol has the advantage of being non-narcotic and having a lower propensity for addiction. Because of its antagonist properties, there appears to be a limit to its depressant effects on respiration.

Adult↗
PubMed1992

Synthesis of N-substituted C-normorphinans and their pharmacological properties.

Several N-substituted C-normorphinans (VIII and IX) were synthesized and tested for their analgetic and narcotic antagonist activities and physical dependence capacity. Treatment of N-formyl- octahydro-2-pyrindine (IIIc) with polyphosphoric acid readily gave N-formyl-C-normorphinan (IV). The N-nor bases (V and VII) obtained from IV were converted to VIII and IX. The N-methyl derivative (I), which was previously reported to be inactive by Haffner's method, exhibited potent analgetic activity by the hot plate method and the AcOH-induced writhing test. Compounds VIII and IX showed pharmacological properties similar to those of N-substituted morphinans and exhibited agonist (analgetic) and/or narcotic antagonist activities. The C-nor analogue (IXa) of cyclorphan (IIc) exhibited potent analgetic and antagonist activities with no physical dependence capacity in the single-dose suppression tests both in rats and monkeys.

Analgesics↗
PubMed1976

[Study on novel morphine antagonists in the animal experiment (author's transl)].

The morphine-antagonistic properties of 5 novel compounds, (--)N-(3-Furylmethyl)-nordesomorphine-hydrochloride-monohydrate (Wa 494-Cl), (--)N-(3-Furylmethyl)-3-hydroxy-morphinan-methansulfonate (Mr 1257 MS), (--)2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-dimethyl-6,7-benzomorphan-methansulfonate (Mr 1452 MS), (+/-)-2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-diethyl-6,7-benzomorphan-hydrochloride (Mr 1302 MS), (--)-N-(3-Furylmethyl)-noroxymorphon-methanesulfonate (Mr 1767 MS), have been examined with different methods on mice and cats. Their properties have been compared with those of naloxone, cyclazocine and nalorphine. The new test compounds showed a profile of action like naloxone.

Analgesia↗
PubMed1975

Oxilorphan (l-N-cyclopropylmethyl-3,14-dihydroxymorphinan): a new synthetic narcotic antagonist.

Oxilorphan is a fully synthetic morphinan derivative containing the 14-hydroxy group characteristics of naloxone and naltrexone. As a narcotic antagonist, oxilorphan was 4 times more potent than dl-cyclazocine, equipotent to naloxone and about one-fourth as potent as naltrexone parenterally. Duration studies in rodents were inconclusive, but in antagonism of morphine analgesia and miosis in the dog, oxilorphan was longer acting than naloxone and equivalent to dl-cyclazocine. Oxilorphan was inactive in the conventional animal thermal analgesic tests. However, oxilone did exhibit relatively weak analgesic activity in preventing phenylquinone-induced abdominal contraction at doses about 700 times higher than those required for antagonist activity. The analgesic potency of oxilorphan was only 120 and 1/300 the potency of morphine and dl-cyclazocine, respectively, but was significantly greater than naltrexone and naloxone. Mice chronically treated with increasing doses of oxilorphan failed to exhibit withdrawal jumping after naloxone challenge. General central nervous system activity studies showed oxilorphan to be relatively free from central side effects at doses at which dl-cyclazocine produced pronounced effects.

Animals↗
PubMedDate not supplied

Alkaloid N-oxides. A review of recent developments.

The preparation, characterization and chemistry of alkaloid N-oxides is reviewed. Because the literature on amine N-oxides is more extensive for animals than for plants, a brief resumé of the pharmacology, metabolism, and toxicity of N-oxides is given. Some 64 naturally occuring N-oxides representing pyrrolidine-piperidine-, pyrrolizidine-, quinolizidine-, tropane-, isoquinoline-, morphinane-, indole- and miscellaneous-type alkaloids are reviewed. These alkaloid N-oxides are additional to and, in the main, have been isolated since those described in a 1971 review. The earlier review dealt with some 56 naturally occurring N-oxides which represented mainly pyrrolizidine and indole types. The role of N-oxides in plants is discussed.

Alkaloids↗
PubMed1979

Comparative gastrointestinal and biliary tract effects of morphine and butorphanol (Stadol).

Butorphanol, levo-N-cyclobutylmethyl-3,14 beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 to 8 times more potent than morphine in experimental animals and man. Butorphanol and morphine were evaluated in mice and dogs for their gastrointestinal and biliary tract smooth muscle effects. Morphine decreased the propulsion of a charcoal meal through the gastrointestinal tract of the mouse in a dose related manner with the maximal inhibition obtainable being 90%. Butorphanol produced a maximal inhibition of motility of only 40% with very high doses producing less of an inhibitory effect than lower doses. In dogs, morphine caused a dose-dependent increase in duodenal smooth muscle activity and a dose-dependent decrease in bile duct flow. A clinically effective i.v. dose of morphine (0.1 mg/kg) produced a statistically significant spasmogenic effect on dog biliary tract and gastrointestinal smooth muscle, while a clinically effective equianalgetic i.v. dose of butorphanol (0.025 mg/kg i.v.) had little or not effect on the biliary or gastrointestinal systems. These findings indicate that at equianalgetic doses, butorphanol should produce less constipation and less biliary tract and gastrointestinal smooth muscle spasm than morphine.

Analgesics↗
PubMed1976

The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic.

Butorphanol, a new, totally synthetic morphinan, which is chemically related to naloxone, has been demonstrated to have both analgesic and narcotic antagonist properties. In rodent antiwrithing analgesic tests, butorphanol was 4 to 30 times more potent than morphine and dl-pentazocine, respectively. As an antagonist, butorphanol was about equivalent to nalorphine and 30 times more potent than dl-pentazocine. On the basis of the naloxone-induced mouse jumping test and the lack of substitution in withdrawn morphine-dependent mice, it is estimated that the potential for physical dependence of butorphanol will be less than that of dl-pentazocine but greater than that of nalorphine and dl-cyclazocine. Animal data also show that agonistic actions of butorphanol, such as respiratory depression and miosis, reach ceiling effects which are lower than those seen with morphine with an increase in dosage. Thus, butorphanol differed from morphine which exhibited agonist effects in a dose-related manner. Butorphanol showed weak to moderate central depressant properties at doses which were considerably higher (greater than 100 X) than those producing analgesia. Minimal cardiovascular and respiratory effects were seen with butorphanol in conscious dogs.

Analgesics↗
PubMed1978

Effect of butorphanol and morphine on pulmonary mechanics, arterial blood pressure and venous plasma histamine in the anesthetized dog.

Butorphanol, levo-N-cyclobutylmethyl-3, 14beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 times more potent than morphine in experimental animals. Equianalgetic doses of butorphanol and morphine were compared, following rapid intravenous injection to anesthetized dogs, for their effects on pulmonary resistance, dynamic compliance, arterial blood pressure and venous plasma histamine levels. Butorphanol, 0.75 mg/kg, had no effect on pulmonary resistance, dynamic compliance or venous plasma histamine levels. Morphine, 3 mg/kg, increased pulmonary resistance, decreased dynamic compliance and elevated venous plasma histamine levels. Both drugs decreased arterial blood pressure but the hypotensive effect of butorphanol was significantly less in magnitude than that of morphine. Pretreatment with chlorpheniramine antagonized the effects of morphine on pulmonary resistance, dynamic compliance and arterial blood pressure. These results suggest that in man butorphanol may have less potential than morphine for causing airway constriction, hypotension and histamine release.

Airway Resistance↗
PubMed1977

Interactions of narcotics and their antagonists with human serum esterase. VI: The behavior of 14-hydroxylated morphine derivatives.

Study of the interaction of 14-hydroxylated morphines and morphinans with human serum esterase revealed behavior similar to that of other morphine derivates as shown by similar acceleratory efficacies and affinity constants. However, 14-hydroxydihydro-6-morphinones showed anomalously low apparent affinities and anomalously high apparent efficacies, while at the same time seemingly interfering with the attachment of another drug to the enzyme. These anomalies are satisfactorily explained by assuming a second receptor site for which only the hydroxyketones have affinity and which interacts with the receptor site common to all opiates and opiate antagonists. Equations derived from this assumption allow to determine the parameters of the interactions of drugs with both receptor sites.

Esterases↗