Discovery of highly potent and selective D4 ligands by interactive SAR study

Mohamed A O Abdelfattah; Jochen Lehmann; Ashraf H Abadi

doi:10.1016/j.bmcl.2013.07.033

Discovery of highly potent and selective D4 ligands by interactive SAR study

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5077-81. doi: 10.1016/j.bmcl.2013.07.033. Epub 2013 Jul 23.

Authors

Mohamed A O Abdelfattah¹, Jochen Lehmann, Ashraf H Abadi

Affiliation

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.

PMID: 23920439
DOI: 10.1016/j.bmcl.2013.07.033

Abstract

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with Ki 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with Ki (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands' arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.

Keywords: D4 ligands; D4 receptors; Dopamine; Interactive SAR study; Phenylpiperazins.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Ligands
Models, Molecular
Molecular Structure
Receptors, Dopamine D4 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Ligands
Receptors, Dopamine D4