Received for publication April 12, 2004.
Revised September 23, 2004.
Accepted for publication September 23, 2004.

Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain

Abstract

We previously demonstrated that in the D4 dopamine receptor the aromatic microdomain that spans the interface of the second and third transmembrane (TM) segments influences the high affinity interactions with the D4-selective ligand L750,667 and the D2-selective ligands methylspiperone, aripiprazole and its congener OPC4392 (Schetz et al., 2000). Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAP) with different subtype-selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands are recognizing this common site. Mutant D4 receptors were constructed by substituting the non-conserved 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 nine of the eleven 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 eleven of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13 to 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.

Key words: Dopamine, Structure-activity relationships and modeling, Homology modeling of signal transduction families, Mutagenesis/Chimeric approaches, Anti-psychotics

This article has been cited by other articles:

				M. A. Al-Fulaij, Y. Ren, M. Beinborn, and A. S. Kopin Identification of Amino Acid Determinants of Dopamine 2 Receptor Synthetic Agonist Function J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 298 - 307. [Abstract] [Full Text] [PDF]

				H. Lan, C. J. DuRand, M. M. Teeter, and K. A. Neve Structural Determinants of Pharmacological Specificity Between D1 and D2 Dopamine Receptors Mol. Pharmacol., January 1, 2006; 69(1): 185 - 194. [Abstract] [Full Text] [PDF]