Mapping the D2/D3 Dopamine Receptor Binding Sites

Summary

Principal Investigator: R R Luedtke
Affiliation: University of North Texas
Country: USA
Abstract: DESCRIPTION (Provided by applicant): A variety of neurological and neuropsychiatric disorders appear to be due to disturbance of the dopaminergic system. Since recent studies indicate that Di-like and D4 dopamine receptor selective antagonists are not effective antipsychotics, there is a renewed focus on D3 dopamine receptors as a target for antipsychotic drugs used in the treatment of schizophrenia. In addition, recent studies suggest that the D3 dopamine receptor subtype might be an important target for the development of agents for pharmacotherapeutics that could be used in the rehabilitation of individuals who abuse cocaine. However, it has been difficult to develop selective D3 receptor compounds that can be used for experimental or clinical studies on the role of the D3 dopamine receptor subtype in neuropsychiatric disorders or drug abuse because the D2 and D3 dopamine receptors have a high degree of amino acid sequence homology within the transmembrane spanning regions, which construct the neutotransmitter binding site. In collaborative studies, our laboratory has identified a series of structurally related compounds that range from 5- to 50-fold selective for the LB compared to the D2 dopamine receptor subtype. The experiments described in this proposal are designed to identify the amino acid residues within the D2 and LB dopamine receptor binding sites that directly interact with the currently available LB selective compounds. This will be accomplished by preparing mutant receptors structurally related to the D2 and LB dopamine receptor subtypes to precisely define the position of the pharmacophore within the neurotranamitter binding site. The results of these studies will 1) provide information on how our current LB dopamine receptor selective compounds bind to the neumtransmitter binding sate and 2) provide additional structural information that will assist us in the design of novel compounds with increased selectivity for LB dopamine receptors
Funding Period: 2001-07-20 - 2006-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Synthesis and characterization of selective dopamine D2 receptor antagonists
    Suwanna Vangveravong
    Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, St Louis, MO 63110, USA
    Bioorg Med Chem 14:815-25. 2006
  2. ncbi Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor
    Peter Grundt
    Medicinal Chemistry Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    J Med Chem 48:839-48. 2005
  3. pmc Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR
    Peter Grundt
    Medicinal Chemistry, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA
    Bioorg Med Chem Lett 17:745-9. 2007
  4. ncbi Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents
    Peter Grundt
    Medicinal Chemistry Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    J Med Chem 50:4135-46. 2007
  5. pmc Structure-activity relationships for a novel series of dopamine D2-like receptor ligands based on N-substituted 3-aryl-8-azabicyclo[3.2.1]octan-3-ol
    Noel M Paul
    Medicinal Chemistry Section, National Institute on Drug Abuses, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA
    J Med Chem 51:6095-109. 2008
  6. pmc N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists
    Amy Hauck Newman
    Medicinal Chemistry Section, National Institute on Drug AbuseIntramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, USA
    J Med Chem 52:2559-70. 2009

Scientific Experts

  • A H Newman
  • Peter Grundt
  • Robert R Luedtke
  • Michelle Taylor
  • Noel M Paul
  • Suwanna Vangveravong
  • Jianjing Cao
  • Elizabeth McElveen
  • Rakesh Kumar
  • Jeffrey R Deschamps
  • Ji Kyung Choi
  • Christina Z Floresca
  • Bruce G Jenkins
  • Sarah Little Jane Husband
  • Katherine M Prevatt
  • Zhude Tu
  • Robert H Mach
  • Jinbin Xu
  • Christina J Bennett
  • Erin E Carlson

Detail Information

Publications6

  1. ncbi Synthesis and characterization of selective dopamine D2 receptor antagonists
    Suwanna Vangveravong
    Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, St Louis, MO 63110, USA
    Bioorg Med Chem 14:815-25. 2006
    ....
  2. ncbi Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor
    Peter Grundt
    Medicinal Chemistry Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    J Med Chem 48:839-48. 2005
    ..The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo...
  3. pmc Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR
    Peter Grundt
    Medicinal Chemistry, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA
    Bioorg Med Chem Lett 17:745-9. 2007
    ..Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity...
  4. ncbi Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents
    Peter Grundt
    Medicinal Chemistry Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    J Med Chem 50:4135-46. 2007
    ..Finally, several structural modifications reduced lipophilicities while retaining the desired binding profile...
  5. pmc Structure-activity relationships for a novel series of dopamine D2-like receptor ligands based on N-substituted 3-aryl-8-azabicyclo[3.2.1]octan-3-ol
    Noel M Paul
    Medicinal Chemistry Section, National Institute on Drug Abuses, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA
    J Med Chem 51:6095-109. 2008
    ..X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes...
  6. pmc N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists
    Amy Hauck Newman
    Medicinal Chemistry Section, National Institute on Drug AbuseIntramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, USA
    J Med Chem 52:2559-70. 2009
    ....