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 The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition
    RenQi Huang
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Tex, USA
    Pharmacology 92:84-9. 2013
  3. pmc Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds
    Robert R Luedtke
    The Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
    ACS Chem Neurosci 3:1050-62. 2012
  4. pmc Molecular determinants of selectivity and efficacy at the dopamine D3 receptor
    Amy Hauck Newman
    Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, United States
    J Med Chem 55:6689-99. 2012
  5. pmc N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity
    Ashwini K Banala
    Medicinal Chemistry Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
    J Med Chem 54:3581-94. 2011
  6. pmc Subtype selectivity of dopamine receptor ligands: insights from structure and ligand-based methods
    Qi Wang
    Division of Radiological Sciences, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, Missouri 63110, USA
    J Chem Inf Model 50:1970-85. 2010
  7. pmc Evaluation of the D3 dopamine receptor selective agonist/partial agonist PG01042 on L-dopa dependent animal involuntary movements in rats
    Lindsay R Riddle
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie, Fort Worth, TX 76107, USA
    Neuropharmacology 60:284-94. 2011
  8. pmc [3H]4-(dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl)benzamide: a selective radioligand for dopamine D(3) receptors. II. Quantitative analysis of dopamine D(3) and D(2) receptor density ratio in the caudate-putamen
    Jinbin Xu
    Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
    Synapse 64:449-59. 2010
  9. pmc Dopamine D3 receptor selective ligands with varying intrinsic efficacies at adenylyl cyclase inhibition and mitogenic signaling pathways
    Michelle Taylor
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76109, USA
    Synapse 64:251-66. 2010
  10. 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
  • Robert R Luedtke
  • Michelle Taylor
  • Peter Grundt
  • Suzy A Griffin
  • Robert H Mach
  • Suwanna Vangveravong
  • Qi Wang
  • Jinbin Xu
  • RenQi Huang
  • Glenn H Dillon
  • Yogesh Mishra
  • Ashwini K Banala
  • David E Reichert
  • Lindsay R Riddle
  • Rakesh Kumar
  • Noel M Paul
  • Zhude Tu
  • Jianjing Cao
  • Elizabeth McElveen
  • Ren Qi Huang
  • Cathy Bell-Horner
  • Sameer S Khatri
  • Rebecca A Roof
  • Benjamin A Levy
  • Cheryse A Furman
  • David R Sibley
  • Babak Hassanzadeh
  • Mark A Mintun
  • Joel S Perlmutter
  • Lynne A Jones
  • Wenhua Chu
  • Jeffrey R Deschamps
  • Katherine M Prevatt
  • Ji Kyung Choi
  • Christina Z Floresca
  • Sarah Little Jane Husband
  • Bruce G Jenkins
  • Christina J Bennett
  • Erin E Carlson

Detail Information

Publications14

  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 The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition
    RenQi Huang
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Tex, USA
    Pharmacology 92:84-9. 2013
    ....
  3. pmc Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds
    Robert R Luedtke
    The Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
    ACS Chem Neurosci 3:1050-62. 2012
    ....
  4. pmc Molecular determinants of selectivity and efficacy at the dopamine D3 receptor
    Amy Hauck Newman
    Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, United States
    J Med Chem 55:6689-99. 2012
    ..These findings are generalizable to other GPCRs in which the SBP can be targeted by bitopic or allosteric ligands...
  5. pmc N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity
    Ashwini K Banala
    Medicinal Chemistry Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
    J Med Chem 54:3581-94. 2011
    ..This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R...
  6. pmc Subtype selectivity of dopamine receptor ligands: insights from structure and ligand-based methods
    Qi Wang
    Division of Radiological Sciences, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, Missouri 63110, USA
    J Chem Inf Model 50:1970-85. 2010
    ..Furthermore, it demonstrates the possibility of being able to apply similar modeling methods to other subtypes or classes of receptors to study GPCR receptor-ligand interactions at a molecular level...
  7. pmc Evaluation of the D3 dopamine receptor selective agonist/partial agonist PG01042 on L-dopa dependent animal involuntary movements in rats
    Lindsay R Riddle
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie, Fort Worth, TX 76107, USA
    Neuropharmacology 60:284-94. 2011
    ....
  8. pmc [3H]4-(dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl)benzamide: a selective radioligand for dopamine D(3) receptors. II. Quantitative analysis of dopamine D(3) and D(2) receptor density ratio in the caudate-putamen
    Jinbin Xu
    Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
    Synapse 64:449-59. 2010
    ..A mathematical model for calculating the absolute densities of dopamine D(2) and D(3) receptors based on the in vitro receptor binding data of [3H]WC-10 and [3H]raclopride was developed...
  9. pmc Dopamine D3 receptor selective ligands with varying intrinsic efficacies at adenylyl cyclase inhibition and mitogenic signaling pathways
    Michelle Taylor
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76109, USA
    Synapse 64:251-66. 2010
    ....
  10. 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
    ....
  11. 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...
  12. 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...
  13. 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...
  14. 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...