DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTS
Principal Investigator: David Nichols
Abstract: DESCRIPTION (provided by applicant): This proposal would continue our longstanding efforts to explore the structure-activity relationships of novel full agonists for the human dopamine D1 receptor. Our past success exploiting the "beta-phenyldopamine" pharmacophore will continue to guide our design efforts for new ligands. Novel ligands to be examined should provide molecular probes not only of the D1/D5 receptors, but also for all of the other dopamine receptor isoforms. The research proposed in this application has three specific aims. First, we seek to expand and develop structure-activity relationships for a new type of DI full agonist that we have just discovered. Second, we propose the synthesis and evaluation of a focused library of small molecules as potential bioisosteres of the catechol function that might lead to an orally-available, noncatechol dopamine DI agonist. Finally, the third aim presents the synthesis of a number of novel ligands that are anticipated to possess dopamine agonist activity. All new ligands will be screened for affinity and functional activity at all five dopamine receptor isoforms. In addition, the data will be used to refine further homology models of the DI and D2 receptors so as to gain a better understanding of the structural features necessary to confer agonist activity and selectivity onto dopaminergic ligands. This model ultimately will be used in structure-based molecule design efforts, as well as to help understand how ligand structure affects receptor function. This work is of particular importance to the mission of NIMH, as the dopamine D1 receptor has been implicated in a number of CNS disorders, including cognitive and memory deficits in schizophrenia. In addition, all of the ligands that we have developed, and propose to develop here, can be custom-tailored by specific structural modifications to provide ligands with a mix of effects at the various dopamine receptor isoforms. Thus, these ligands represent novel molecular probes for dopamine receptors, as well as being potential new therapies for CNS disorders that involve dysfunction in dopamine pathways. Dopamine is a critical neurotransmitter in brain areas involved in mood regulation, drug addiction, movement disorders, and memory and cognition, among others. Our work will generate molecular probes that should help to increase our understanding of these pathways, and may also provide new therapies for disorders such as Parkinson's disease and schizophrenia.
Funding Period: ----------------1987 - ---------------2011-
more information: NIH RePORT
- trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonistJuan Pablo Cueva
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA
J Med Chem 49:6848-57. 2006..The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the beta-phenyldopamine pharmacophore template...
- Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D₃ receptor-selective full agonist ligandAlia H Clark
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Integrative Neuroscience Program, Purdue University, West Lafayette, IN 47907, USA
Bioorg Med Chem 20:6366-74. 2012..Furthermore, n-propyl analog 5f was found to be a high affinity (K(i)=1.1 nM) D(3) dopamine full agonist with 145-fold selectivity over the D(2) receptor and about 840-fold selectivity over the D(1) receptor...
- Comparison of the enantiomers of (+/-)-doxanthrine, a high efficacy full dopamine D(1) receptor agonist, and a reversal of enantioselectivity at D(1) versus alpha(2C) adrenergic receptorsJulie A Przybyla
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Eur Neuropsychopharmacol 19:138-46. 2009..These findings demonstrate a reversed stereoselectivity for the enantiomers of DOX at D(1) and alpha(2C) receptors and have implications for the therapeutic utility of doxanthrine...
- Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonistsLisa A Bonner
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States
Bioorg Med Chem 18:6763-70. 2010..Importantly, we demonstrate that the 7,8-dihydroxy-5-phenyl-substituted ligand is an extremely potent, high-affinity, full D1 dopamine receptor-selective agonist...
- Mapping the catechol binding site in dopamine D₁ receptors: synthesis and evaluation of two parallel series of bicyclic dopamine analoguesLisa A Bonner
Department of Chemistry, Saint Anselm College, Manchester, NH 03102, USA
ChemMedChem 6:1024-40. 2011..Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D₁-like receptor potency and selectivity are restored...
- Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7α-, 7β-, 8α-, and 8β-methyl substituted dihydrexidine analoguesJuan Pablo Cueva
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
J Med Chem 54:5508-21. 2011..51) is the cause for the 14-fold loss in affinity associated with 8β-axial substitution, unfavorable steric interactions with Ser107(3.36) result in the more dramatic decreases in binding affinity suffered by the rest of the analogues...
- Assessment of dopamine D₁ receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393Alia H Clark
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
Bioorg Med Chem 19:5420-31. 2011..These results suggest that the conformationally-restricted structure of the analogs cannot adopt a binding orientation that is necessary for agonist activity...
- Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridinesJuan Pablo Cueva
Quimique Cía Ltda, P O Box 17 07 9009, Quito, Ecuador
Eur J Med Chem 48:97-107. 2012....
- Ligand-specific roles for transmembrane 5 serine residues in the binding and efficacy of dopamine D(1) receptor catechol agonistsBenjamin R Chemel
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907 2091, USA
Mol Pharmacol 81:729-38. 2012..These results provide a new understanding of the complexities of D(1) ligand recognition and agonist activation and have implications for the design of rigid catechol ligands...