Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D(2)-like receptors

Ismail Salama; Stefan Löber; Harald Hübner; Peter Gmeiner

doi:10.1016/j.bmcl.2014.06.079

Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D(2)-like receptors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3753-6. doi: 10.1016/j.bmcl.2014.06.079. Epub 2014 Jul 3.

Authors

Ismail Salama¹, Stefan Löber², Harald Hübner², Peter Gmeiner³

Affiliations

¹ Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt.
² Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany.
³ Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.

PMID: 25047579
DOI: 10.1016/j.bmcl.2014.06.079

Abstract

Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.

Keywords: Binding affinity; Bivalent ligands; D(2) receptor; D(3) receptor; D(4) receptor; Dopamine; GPCR dimers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites / drug effects
Dose-Response Relationship, Drug
Haloperidol / chemical synthesis
Haloperidol / chemistry
Haloperidol / pharmacology*
Humans
Ligands
Molecular Structure
Receptors, Dopamine D2 / metabolism*
Structure-Activity Relationship

Substances

Ligands
Receptors, Dopamine D2
Haloperidol