ALCOHOL AND DRUG ABUSE RESEARCH CENTER
Medicinal Chemistry Laboratory
Research Summary
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The Medicinal Chemistry Laboratory, directed by Professor John L. Neumeyer, has focused on developing novel chemical entities that can be used as molecular tools to modulate the activity of a variety of G-protein Coupled Receptors found in the central nervous system. Specifically:
- Development of mixed kappa and mu opioid receptor ligands as an alternative approach to cocaine abuse
There is increasing evidence that kappa agonists, except their antinociceptive effects as analgesics, also attenuate a number of neurobiological effects of cocaine. For example, kappa agonists can reduce cocaine self-administration in rodents and nonhuman primates although some side effects are also observed. However, mixed kappa/mu agonists appear to offer some advantages as potential treatments for cocaine abuse. Both acute and chronic treatment with the mixed kappa/mu opioids - cyclorphan and its N-cyclobutylmethyl derivative (MCL-101, butorphan), reduced cocaine self-administration dose-dependently and produced fewer side effects (transient salivation) than kappa-selective agonists (sedation, salivation and emesis). These promising results encouraged us to further synthesize a series of novel modified morphinan analogues, based on the structures of cyclorphan and butorphan. - Development of Innovative Diagnostic Techniques
The biological action of cocaine is believed to interact at a number of brain receptors and transporters, and changes in these receptors and transporters are believed to be responsible for a number of psychiatric disorders. Unfortunately, the functions of these proteins and their mechanisms of action are still largely unknown. To discover an effective technique to "visualize" these proteins, and further diagnose the brain disorder resulting from any changes in these proteins, efforts in developing innovative imaging agents for Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT) and Magnetic Resonance Imaging (MRI) are underway. Such methods will enhance our understanding of neuropsychiatric disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), and other common neuropsychiatric conditions. Special emphasis has been directed toward the synthesis of novel ligands for dopamine receptors and transporters as well as kappa and mu opioid agonists and antagonists. - Development of highly potent and selective ligands for dopamine receptor (transporter) or subtypes of dopamine receptor (D1, D2, D3, D4, D5)
Recent reports suggested the failure of dopamine agonists/antagonists or dopamine reuptake transporter inhibitors responsible for cocaine reward/reinforcement may be ascribed to their low selectivity for dopamine over serotonin or norepinephrine receptors. Although five subtypes of dopamine receptors were found and cloned recently, their structures and functions are unknown. Our efforts in this area mainly focus on the synthesis and evaluation of novel ligands, which are selective D1 or D2 agonists. Such agents will also be useful for evaluating the etiology and progress of Parkinson's disease in human brains.
Collaborators
- Department of Pharmacology and Physiology directed by Dr. Jean Bidlack at the University of Rochester School of Medicine
- Behavioral, Pharmacological, and Neurobiological Science Laboratories directed by Dr. Nancy K. Mello, Dr. Jack Bergman, and Dr. Jenn Newman at the Alcohol and Drug Abuse Research Center, McLean Hospital
- Neuropharmacology Laboratory directed by Ross Baldessarini, MD and Frank Tarazi, Ph.D. at Mailman Research Center, McLean Hospital
- National Center for Microscopy Research directed by Dr. Mark Ellisman, University of California, San Diego, CA.
- Shanghai Institute of Materia Medica, Synthetic Organic and Medicinal Chemistry Laboratory, directed by Dr. Ao Zhang
- Department of Toxicology, University of Cagliari, Italy, directed by Dr. Gianfranco Balboni
- Vanderbilt University Medical Center, Dr. Ronald Baldwin
Personnel
- John L. Neumeyer, Ph.D. - Director, Medicinal Chemistry Laboratory; Professor of Medicinal Chemistry (Emeritus)
- Chris Hupp, Ph. D. - NIDA Research Fellow
- Anna W. Sromek, Ph. D. - NIDA Research Fellow
- Bin Zhang, Ph. D. - Research Fellow
- Tangzhi Zhang, Ph. D. - Research Fellow
Research Support
- National Institute on Drug Abuse (NIDA)
- National Institute of Neurological Disorders and Stroke (NINDS)
- The Branfman Family Foundation
- Zhang A, Neumeyer JL: Microwave-Promoted Pd-Catalyzed Cyanation of Aryl Triflates: A Fast and Versatile Access to 3-Cyano-3-desoxy-10-ketomorphinans. Organic Lett. 2003, 5, 201-203.
- Zhang A, Vliet AV, Neumeyer JL: Synthesis of Aminothiazole Derived Morphinans. Tetrahedron Lett. 2003, 44: 6459-6462.
- Neumeyer JL, Kula NS, Bergman J, Baldessarini R: Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines. Eur. J. Pharmacol. 2003, 474, 137-140.
- Neumeyer JL, Zhang A, Xiong W, Gu X, Hilbert JE, Knapp BI, Negus SS, Mello NK, Bidlack JM: Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors. J. Med. Chem. 2003, 46, 5162-5170.
- Csutoras C, Zhang A, Zhang K, Kula NS, Baldessarini RJ, Neumeyer JL: Synthesis and neuropharmacological evaluations of substituted R-(-)-11-hydroxyaporphines. Bioorganic and Med. Chem. 2004, 3553-3559.
- Zhang A, Xiong X, Bidlack JM, Hilbert JE, Knapp BI, Wentland MP and Neumeyer JL, 10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed k and m opioid ligands: Synthesis and biological evaluation of their binding affinity at opioid receptors. J Med Chem 2004, 47, 165-174.
- Peng X, Zhang A, Kula NS, Baldessarini J and Neumeyer JL, Synthesis and amine transporter affinities of novel phenyltropane derivatives as positron emission tomography (PET) imaging agents. Bioorganic and Med Chem Lett. 2004, 14, 5635-5639.
- Zhang, A., Kula, N.S., Zhang, K, Baldessarini, R.J., Kaufman, M.J., Renshaw, P.F., and Neumeyer, J.L.: Development of polyfluorophenyltropanes: Potential probes for 19F magnetic resonance imaging (MRI) and spectroscopy (MRS) assessments of the dopamine transporter. Letters in Drug Design & Discovery, 2005, 2, 302-306.
- Zhang, A., Csutoras, C., Zong, R. and Neumeyer, J.L.: Synthesis of 2-fluoro-11-hydroxy-N-propylnoraporphine: A potential dopamine D2 agonist. Organic Letters, 2005, 7, 3239-3242.
- Peng, X., Knapp, B.I., Bidlack, J.M. and Neumeyer, J.L.: Synthesis and preliminary in vitro investigation of bivalent ligands containing homo- and heterodimeric pharmacophores at µ, δ, and κ opioid receptors. J. Med. Chem. 2006, 49, 256-262.
- Neumeyer, J.L., Peng, X., Knapp, B.I., Bidlack, J.M., Lazurus, L.H., Salvadori, S., Trapella, C. and Balboni, G.: New opioid designed multiple ligand from Dmt-Tic and morphinan pharmacophores. J. Med. Chem. 2006, 49, 5640-5643.
- Zhang, A., Neumeyer, J.L. and Baldessarini, R.J.: Recent progress in development of dopamine receptor subtype-selective agents: Potential therapeutic agents for neurological and psychiatric disorders. Chem. Revs., 2007, 107, 274-302.
- Zhang, A., Zhang, Y., Branfman, A.R., Baldessarini, R.J. and Neumyer, J.L.: Advances in development of dopaminergic aporphinoids. A J. Med. Chem. 2007, 50, 171-181.
- Peng, X. and Neumeyer, J.L.: Kappa receptor bivalent ligands. Current Topics in Medicinal Chemistry, 2007, 7, 363-373.
- Peng, X., Knapp, B.I., Bidlack, J.M. and Neumeyer, J.L.: High-affinity carbamate analogues of morphinan at opioid receptors. Bioorganic & Medicinal Chemistry Letters, 2007, 17, 1508-1511.
- Wuest, F., Berndt, M., Strobel, K., van den Hoff, J., Peng, X., Neumeyer, J.L. and Bergmann, R.: Synthesis and radiopharmacological characterization of 2β-carbo-2’-[18F]fluoroethoxy-3β-(4-bromo-phenyl)tropane ([18F]MCL-322) as a novel PET radiotracer for imaging the dopamine transporter (DAT). Bioorganic & Medicinal Chemistry, 2007,15, 4511-4519.
- Peng, X., Knapp, B.I., Bidlack, J.M. and Neumeyer, J.L.: Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone and naloxone at μ, δ, and κ opioid receptors. J. Med. Chem. 2007, 50, 2254-2258.
- Peng, X., Knapp, B.I., Bidlack, J.M. and Neumeyer, J.L.: In-vitro investigation of oxazol and urea analogues of morphinan at opioid receptors. Bioorganic Medicinal Chemistry 2007, 15, 4106-4112.
- Si, Y.-G., Gardner, M.P., Tarazi, F.I., Baldessarini, R.J. and Neumeyer, J.L.: R-(–)-N-alkyl-11-hydroxy-10-hydroxymethyl- and 10-methyl-aporphines as 5-HT1A receptor ligands. Bioorganic & Medicinal Chemistry Letters 2007, 17, 4128-4130.
- Si,Y-G. and Neumeyer,J.L.: Facile synthesis of 2-methoxy-11-hydroxyaporphine: A potential dopamine D1 receptor ligand.Synthesis, 2007,24,3787-3790.
- Si,Y-G.,Gardner,M.P.,Tarazi, F.I.,Baldessarini,R.J.: Synthesis and dopamine receptor affinities of N-alkyl 11-hydroxy-2-methoxynoraporphine: N-Alkyl substituents determine D1 versus D2 Receptor selectivity. J.Med Chem. 2008, 51(4), 983-7.
- Fulton B.S., Knapp,B.I., Bidlack J.M.,Neumeyer J.L.: Synthesis and pharmacological evaluation of hydrophobic esters and ethers of butorphanol at opioid receptors. Bioorg. Med. Chem. Lett. 2008, 18, 4474-4476.
- Mathews, J.L., Fulton, B.S., Negus, S.S., Neumeyer, J.L. and Bidlack, J.M.: In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: Isomeric, bivalent ligands with mu/kappa agonist properties. Neurochem. Res. 2008, 33, 2142-2150.
- Si, Y.-G., Gardner, M.P., Tarazi, F.I., Baldessarini, R.J. and Neumeyer, J.L.: Synthesis and binding studies of 2-O-and 11-O-substituted N-alkylnoraporphines. Bioorganic & Medicinal Chemistry Letters, 2008, 18, 3971-3973.
- Decker, M., Fulton, B.S., Zhang B., Knapp, B.I., Bidlack, J.M. and Neumeyer, J.L.: Univalent and bivalent ligands of butorphan: Characteristics of the linking chain determine the affinity and potency of such opioid ligands. J. Med Chem., 2009, 52, 7389-7396.
- Decker, M., Si, Y.-G., Knapp, B.I., Bidlack, J.M. and Neumeyer, J.L.: Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: Ligands for mu, kappa and delta opioid receptors. J. Med Chem., 2009, 52, (DOI: 10.1021/jm9013482).
- Balboni, G.; Salvadori, S.; Trapella, C.; Knapp, B. I.; Bidlack, J. M.; Lazarus, L. H.; Peng, X.; Neumeyer, J. L.Evolution of the Bifunctional Lead μ Agonist/δ Antagonist Containing the 20,60-Dimethyl-L-tyrosine-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt-Tic) Opioid Pharmacophore. ACS Chem. Neurosci. 2009, (DOI: 10.1021/cn900025j).
