Journal article
Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain
Molecular pharmacology, v 66(6), pp 1491-1499
Dec 2004
PMID: 15448188
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Abstract
We previously demonstrated that, in the D4 dopamine receptor, the aromatic microdomain that spans the interface of the second and third transmembrane segments influences the high-affinity interactions with the D4-selective ligand L750,667 [3-[[4-(4-iodophenyl) piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine] and the D2-selective ligands methylspiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl) piperazinyl) propoxy] 2-(1H)-quinolinone] (Schetz et al., 2000). Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) with different subtype selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands recognize this common site. Mutant D4 receptors were constructed by substituting the nonconserved amino acid(s) from the corresponding locations in the D2 receptor. The D4-L2.60W, D4-F2.61V, and D4-LM3.28-3.29FV substitutions result in alterations of the relative position of members of the aromatic microdomain. From these results and molecular models of the ligand-receptor complexes, we conclude that 9 of the 11 D4-selective 1,4-DAPs, including L750,667, have a common pattern of ligand-receptor recognition that depends upon favorable interactions with the phenylalanine at position 2.61 (D4-F2.61V, 20-96-fold decrease). Like methylspiperone, aripiprazole, and OPC4392, the two D4-selective 1,4-DAPs that are insensitive to the D4-F2.61V mutation are sensitive to aromatics at position 2.60 (D4-L2.60W, 7-20-fold increase), and they all have longer spacer arms that permit their tethered aromatics to adopt alternative orientations in the binding-site crevice. All 11 of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13-494-fold decrease) but not the moderately D2-selective methylspiperone. The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs.
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Details
- Title
- Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain
- Creators
- Sandhya Kortagere - Department of Physiology & Biophysics, Weill Medical College of Cornell University, New York, New York, USAPeter GmeinerHarel WeinsteinJohn A Schetz
- Publication Details
- Molecular pharmacology, v 66(6), pp 1491-1499
- Publisher
- American Society for Pharmacology and Experimental Therapeutics (ASPET); United States
- Grant note
- R01 MH063162 / NIMH NIH HHS K05 DA000060 / NIDA NIH HHS K05 DA000060-26 / NIDA NIH HHS R01 MH063162-06 / NIMH NIH HHS P20 RR017701-01 / NCRR NIH HHS R01-MH063162-01 / NIMH NIH HHS P20 RR017701 / NCRR NIH HHS K05-DA00060 / NIDA NIH HHS R01 MH063162-01A2 / NIMH NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000225309900013
- Scopus ID
- 2-s2.0-9444228286
- Other Identifier
- 991014878639104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy