Journal article
Interaction of novel hybrid compounds with the D3 dopamine receptor: Site-directed mutagenesis and homology modeling studies
Biochemical pharmacology, v 81(1)
2011
PMID: 20833147
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The dopamine D3 receptor has been implicated as a potential target for drug development in various complex psychiatric disorders including psychosis, drug dependence, and Parkinson's disease. In our overall goal to develop molecules with preferential affinity at D3 receptors, we undertook a hybrid drug development approach by combining a known dopamine agonist moiety with a substituted piperazine fragment. In the present study, three compounds produced this way with preferential D3 agonist activity, were tested at D3 receptors with mutations in the agonist binding pocket of three residues known to be important for agonist binding activity. At S192A and T369V, the hybrid agonist compounds produced an interaction profile in [
3H]spiperone binding assays similar to that of the parent 5-OH-DPAT and 7-OH-DPAT molecules. The loss of affinity at the S192A mutant was most prominent for 5-OH-DPAT and its corresponding hybrid compound D237. D110N did not show any radioligand binding. Homology modeling indicated that 7-OH-DPAT-derived D315 uniquely shares H-bonding with Tyr365 which produced favorable interaction and no loss of H-bonding in the S192A mutant, suggesting that agonist activity may not be solely controlled by residues in the binding pocket.
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Details
- Title
- Interaction of novel hybrid compounds with the D3 dopamine receptor: Site-directed mutagenesis and homology modeling studies
- Creators
- Sandhya Kortagere - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USAShu-Yuan Cheng - Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USATamara Antonio - Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USAJuan Zhen - Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USAMaarten E.A Reith - Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USAAloke K Dutta - Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA
- Publication Details
- Biochemical pharmacology, v 81(1)
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000285033600017
- Scopus ID
- 2-s2.0-78549284860
- Other Identifier
- 991014877834504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy