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ALCOHOL AND DRUG ABUSE RESEARCH CENTER

Medicinal Chemistry Laboratory

Research Summary

Medicinal Chemistry Laboratory Staff

The Medicinal Chemistry Laboratory Staff
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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:

  1. 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.
  2. 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.
  3. 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.

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Representative Publications

04.2010