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1531-12-0Relevant academic research and scientific papers
Preliminary pharmacological evaluation of enantiomeric morphinans
Sromek, Anna W.,Provencher, Brian A.,Russell, Shayla,Chartoff, Elena,Knapp, Brian I.,Bidlack, Jean M.,Neumeyer, John L.
, p. 93 - 99 (2014/03/21)
A series of levo- and dextromorphinan pairs have been synthesized and evaluated for their affinities to the mu, kappa, and delta opioid receptors, the N-methyl-d-aspartate (NMDA) channel, and sigma 1 and 2 receptors. It was found that levo isomers tended to have higher affinities at the opioid receptors and moderate to high affinities to the NMDA and sigma receptors, while dextro isomers tended to have lower affinities to the opioid receptors but comparatively higher affinities to the NMDA and sigma receptors. This series of compounds have interesting and complex pharmacological profiles, and merit further investigation as potential therapies for drug abuse treatment.
Exploration of catalytic properties of CYP2D6 and CYP3A4 through metabolic studies of levorphanol and levallorphan
Bonn, Britta,Masimirembwa, Collen M.,Castagnoli Jr., Neal
experimental part, p. 187 - 199 (2010/12/24)
CYP2D6 and CYP3A4, two members of the cytochrome P450 superfamily of monooxygenases, mediate the biotransformation of a variety of xenobiotics. The two enzymes differ in substrate specificity and size and characteristics of the active site cavity. The aim of this study was to determine whether the catalytic properties of these isoforms, reflected by the differences observed from crystal structures and homology models, could be confirmed with experimental data. Detailed metabolite identification, reversible inhibition, and time-dependent inhibition were examined for levorphanol and levallorphan with CYP2D6 and CYP3A4. The studies were designed to provide a comparison of the orientations of substrates, the catalytic sites of the two enzymes, and the subsequent outcomes on metabolism and inhibition. The metabolite identification revealed that CYP3A4 catalyzed the formation of a variety of metabolites as a result of presenting different parts of the substrates to the heme. CYP2D6 was a poorer catalyst that led to a more limited number of metabolites that were interpreted in terms to two orientations of the substrates. The inhibition studies showed evidence for strong reversible inhibition of CYP2D6 but not for CYP3A4. Levallorphan acted as a time-dependent inhibitor on CYP3A4, indicating a productive binding mode with this enzyme not observed with CYP2D6 that presumably resulted from close interactions of the N-allyl moiety oriented toward the heme. All the results are in agreement with the large and flexible active site of CYP3A4 and the more restricted active site of CYP2D6. Copyright
Anticonvulsant effects of new morphinan derivatives
Kim, Hyoung-Chun,Nabeshima, Toshitaka,Jhoo, Wang-Kee,Ko, Kwang Ho,Kim, Won-Ki,Shin, Eun-Joo,Cho, Minkyoung,Lee, Phil Ho
, p. 1651 - 1654 (2007/10/03)
We synthesized a series of compounds that are modified in positions 3 and 17 of the morphinan ring system, with the intention of developing ideal anticonvulsant agents. We examined the effects of these compounds on kainic acid (KA)-induced seizures, and on locomotor patterns in rats. We found that compounds 5, 6, and 8 exhibit novel anticonvulsant effects, with negligible psychotropic effects.
Mixed κ agonists and μ agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: Synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan
Neumeyer, John L,Gu, Xiao-Hui,Van Vliet,DeNunzio, Nicholas J,Rusovici, Daniela E,Cohen, Dana J,Negus,Mello, Nancy K,Bidlack, Jean M
, p. 2735 - 2740 (2007/10/03)
A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (μ, δ, and κ) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the μ and κ opioid receptors was observed. All of these novel derivatives showed a preference for the μ and κ versus δ binding.
Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: Mixed κ agonists and μ agonists/antagonists as potential pharmacotherapeutics for cocaine dependence
Neumeyer, John L.,Bidlack, Jean M.,Zong, Rushi,Bakthavachalam, Venkatesalu,Gao, Peng,Cohen, Dana J.,Negus, S. Stevens,Mello, Nancy K.
, p. 114 - 122 (2007/10/03)
This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of K agonists related to the morphinan (-)- cyclorphan (3a) and the benzomorphan (-)cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at κ opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N- cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)- mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for μ, δ, and κ opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the κ receptor than for the μ receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only 4-fold greater affinity for the κ receptor in comparison to the δ receptor. These findings were confirmed in the antinociceptive tests (tail- flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the δ receptor while 3b did not produce agonist or antagonist effects at the δ receptor. Both 3a,b had comparable κ agonist properties 3a,b had opposing effects at the μ receptor: 3b was a μ agonist whereas 3a was a μ antagonist.
Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse
Neumeyer, John L.,Mello, Nancy K.,Stevens Negus,Bidlack, Jean M.
, p. 337 - 344 (2007/10/03)
Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, L-cyclorphan (3a) and the benzomorphan, L-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a-c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments L-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (μ), delta (δ) and kappa (κ) opioid receptors. Both 3a and 3b were more selective for the κ receptor than the μ receptor. However, 3b was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the κ receptor in comparison to the δ receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were κ agonists. Correlating with the binding results, compound 3a had some δ agonist properties, while 3b was devoid of any activity at the δ receptor. In addition, compounds 3a and 3b had opposing properties at the μ opioid receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. Copyright (C) 2000 Elsevier Science B.V.
Dextrorphan. Note II. Preparation of dextrorphan citrate
Passarotti,Valenti,Grianti
, p. 475 - 477 (2007/10/02)
Preparation of destrorphan citrate, a very soluble salt in water, in described. This salt may be used in oral composition with anti-tussive activity. Structural date are reported about 1H-NMR, 13C-NMR, COSY.