- Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: Mixed κ agonists and μ agonists/antagonists as potential pharmacotherapeutics for cocaine dependence
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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.
- Neumeyer, John L.,Bidlack, Jean M.,Zong, Rushi,Bakthavachalam, Venkatesalu,Gao, Peng,Cohen, Dana J.,Negus, S. Stevens,Mello, Nancy K.
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- Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse
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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.
- Neumeyer, John L.,Mello, Nancy K.,Stevens Negus,Bidlack, Jean M.
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- METHODS FOR PREPARING LEVORPHANOL AND RELATED COMPOUNDS, AND COMPOSITIONS THEREOF
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A method for producing substantially pure levorphanol and related compounds, when compared to the conventional process, is provided. In particular, a method for producing substantially pure levorphanol tartrate dihydrate is described. Also described are compositions comprising levorphanol and related compounds, particularly compositions comprising levorphanol tartrate dihydrate, levomethorphan, and norlevorphanol in which the levomethorphan and norlevorphanol are present in the composition in reduced levels.
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Paragraph 0177-0182
(2020/04/29)
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- MORPHAN AND MORPHINAN ANALOGUES, AND METHODS OF USE
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The present application relates to analogues of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof.
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Page/Page column 76
(2014/12/12)
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