Bivalent dopamine D2 receptor ligands: synthesis and binding properties.

Article Details

Citation

Copy to clipboard

Kuhhorn J, Hubner H, Gmeiner P

Bivalent dopamine D2 receptor ligands: synthesis and binding properties.

J Med Chem. 2011 Jul 14;54(13):4896-903. doi: 10.1021/jm2004859. Epub 2011 Jun 3.

PubMed ID

21599022 [ View in PubMed

]

Abstract

Dopamine D(2) receptor homodimers might be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising target proteins for the discovery of atypical antipsychotics. A highly attractive approach to investigate and control GPCR dimerization may be provided by the exploration and characterization of bivalent ligands, which can act as molecular probes simultaneously binding two adjacent binding sites of a dimer. The synthesis of bivalent dopamine D(2) receptor ligands of type 1 is presented, incorporating the privileged structure of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) and triazolyl-linked spacer elements. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for bivalent ligands with particular spacer lengths and a comparative analysis with respective monovalent control ligands and unsymmetrically substituted analogues indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Haloperidol	Dopamine D2 receptor	Ki (nM)	1.5	N/A	N/A	Details
Haloperidol	Dopamine D2 receptor	Ki (nM)	1.1	N/A	N/A	Details
Haloperidol	Dopamine D3 receptor	Ki (nM)	6.3	N/A	N/A	Details