Preliminary pharmacological evaluation of enantiomeric morphinans.

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.

[1]  J. Neumeyer,et al.  Synthesis and pharmacological evaluation of aminothiazolomorphinans at the mu and kappa opioid receptors. , 2013, Journal of medicinal chemistry.

[2]  S. Maier,et al.  Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement , 2012, The Journal of Neuroscience.

[3]  B. Cohen,et al.  Repeated Exposure to the κ-Opioid Receptor Agonist Salvinorin A Modulates Extracellular Signal-Regulated Kinase and Reward Sensitivity , 2011, Biological Psychiatry.

[4]  Allison T. Knoll,et al.  Dynorphin, stress, and depression , 2010, Brain Research.

[5]  M. Decker,et al.  Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: ligands for mu, kappa, and delta opioid receptors. , 2010, Journal of medicinal chemistry.

[6]  Александр Алексеевич Спасов,et al.  Kappa-opioid agonist , 2009 .

[7]  T. Shippenberg.  The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders? , 2009, Neuropsychopharmacology.

[8]  B. Cohen,et al.  The Kappa-Opioid Agonist U69,593 Blocks Cocaine-Induced Enhancement of Brain Stimulation Reward , 2008, Biological Psychiatry.

[9]  W. Carlezon,et al.  Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation , 2007, Nature Protocols.

[10]  Jau-Shyong Hong,et al.  Stereoselective action of (+)-morphine over (-)-morphine in attenuating the (-)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse. , 2007, European journal of pharmacology.

[11]  J. Neumeyer,et al.  Synthesis and preliminary in vitro investigation of bivalent ligands containing homo- and heterodimeric pharmacophores at μ, δ, and κ opioid receptors , 2006 .

[12]  N. Chatterjie,et al.  Prevention of cocaine-induced hyperactivity by a naloxone isomer with no opiate antagonist activity , 1996, Neurochemical Research.

[13]  J. Neumeyer,et al.  Synthesis of aminothiazole derived morphinans , 2003 .

[14]  N. Mello,et al.  Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys , 2003, Neuropsychopharmacology.

[15]  F. Tortella,et al.  Attenuation of the stimulant and convulsant effects of cocaine by 17-substituted-3-hydroxy and 3-alkoxy derivatives of dextromethorphan , 2003, Pharmacology Biochemistry and Behavior.

[16]  N. Mello,et al.  Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys. , 2003, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[17]  A. Svingos,et al.  κ-Opioid and NMDA glutamate receptors are differentially targeted within rat medial prefrontal cortex , 2002, Brain Research.

[18]  E. Shin,et al.  Anticonvulsant effects of new morphinan derivatives. , 2001, Bioorganic & medicinal chemistry letters.

[19]  S. D. Glick,et al.  Comparative effects of dextromethorphan and dextrorphan on morphine, methamphetamine, and nicotine self-administration in rats. , 2001, European journal of pharmacology.

[20]  J. Morley,et al.  d-Morphine, but not l-morphine, has low micromolar affinity for the non-competitive N-methyl-d-aspartate site in rat forebrain. Possible clinical implications for the management of neuropathic pain , 2000, Neuroscience Letters.

[21]  N. Mello,et al.  Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse. , 2000, Pharmaceutica acta Helvetiae.

[22]  N. Mello,et al.  Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence. , 2000, Journal of medicinal chemistry.

[23]  Yueh-Ching Chou,et al.  Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan , 1999, Brain Research.

[24]  N. Chatterjie,et al.  Dextro-Naloxone Counteracts Amphetamine-Induced Hyperactivity , 1998, Pharmacology Biochemistry and Behavior.

[25]  P Riederer,et al.  Quantitative analysis of the structural requirements for blockade of the N-methyl-D-aspartate receptor at the phencyclidine binding site. , 1998, Journal of medicinal chemistry.

[26]  K. A. Trujillo.  Effects of Noncompetitive N-Methyl-D-Aspartate Receptor Antagonists on Opiate Tolerance and Physical Dependence , 1995, Neuropsychopharmacology.

[27]  K. Elliott,et al.  N-Methyl-D-Aspartate (NMDA) Receptors, Mu and Kappa Opioid Tolerance, and Perspectives on New Analgesic Drug Development , 1995, Neuropsychopharmacology.

[28]  R. Shank,et al.  Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. , 1995, The Journal of pharmacology and experimental therapeutics.

[29]  A. Gratton,et al.  Effects of local delta and mu opioid receptor activation on basal and stimulated dopamine release in striatum and nucleus accumbens of rat: An in vivo electrochemical study , 1991, Neuroscience.

[30]  Li Chen,et al.  Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a μ opioid , 1991, Neuron.

[31]  H. Saji.  [Opioid receptor]. , 1991, Nihon rinsho. Japanese journal of clinical medicine.

[32]  A. Brossi,et al.  Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone. , 1978, Journal of medicinal chemistry.

[33]  T. Prisinzano,et al.  Opioid Receptor Ligands , 2022, Burger's Medicinal Chemistry and Drug Discovery.