Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding.

Ehrlich K, Götz A, Bollinger S, Tschammer N, Bettinetti L, Härterich S, Hübner H, Lanig H, Gmeiner P (2009)

Publication Type: Journal article, Original article

Publication year: 2009

Journal

Original Authors: Ehrlich K., Gotz A., Bollinger S., Tschammer N., Bettinetti L., Harterich S., Hubner H., Lanig H., Gmeiner P.

Publisher: American Chemical Society

Book Volume: 52

Pages Range: 4923-4935

Journal Issue: 15

DOI: 10.1021/jm900690y

Abstract

Assembling phenylpiperazines with 7a-azaindole via different spacer elements, we developed subtype selective dopamine receptor ligands of types 1a,c, 2a, and 3a preferentially interacting with D, D, and D, respectively. To complete this set, the methylthio analogues 2b and 3b exceeding the affinity of 2a and 3a by one order of magnitude and the structural intermediate 1b were synthesized. These chemically similar but biologically divergent target compounds served as molecular probes for radioligand displacement experiments, mutagenesis, and docking studies on homology models based on the recent crystal structure of the β-adrenergic receptor. Specific interactions with the highly conserved amino acids Asp and His and less conserved residues at positions 2.61, 2.64, 3.28, and 3.29 were identified. Inclusion of a carefully modeled extracellular loop 2 displayed two nonconserved residues in EL2 that differently contribute to ligand binding. Obviously, subtype selectivity is caused by non-conserved but frequently mediated by conserved amino acids. © 2009 American Chemical Society.

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How to cite

APA:

Ehrlich, K., Götz, A., Bollinger, S., Tschammer, N., Bettinetti, L., Härterich, S.,... Gmeiner, P. (2009). Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding. Journal of Medicinal Chemistry, 52(15), 4923-4935. https://doi.org/10.1021/jm900690y

MLA:

Ehrlich, Katharina, et al. "Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding." Journal of Medicinal Chemistry 52.15 (2009): 4923-4935.

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