| dc.description.abstract | Dopamine, a small neurotransmitter released by the brain, plays a major role in the body's reward and motivation systems. Dopamine interacts with a class of G-Protein coupled receptors-- D1R through D5R-- to propagate or mitigate the dopamine signaling effect. Specifically, D2R and D3R play a role in the perpetuation of cocaine addiction. Due to the high sequence similarities between D2R and D3R, it represents a major challenge to develop selective ligands for each type of receptor. Carboranes are neutral and lipophilic icosahedral clusters composed of BH and CH vertices with the general formula C2B10H12. The carborane moiety has been demonstrated to be bioisosteric to the phenyl group. It is robust, stable to metabolism, and is capable of forming multiple H-bonding interactions with the biological target. In this project we determined to justify the use of a carborane moiety in design of dopamine receptor ligands. The known D3R antagonist eticlopride combines the ethylpyrrolidinelmethyl moiety and substituted phenyl group via the amide linkage. Recently reported crystal structure of the D3 receptor with its antagonist eticlopride revealed a range of crucial interactions within the orthosteric binding site, the most important of which is a salt bridge between tertiary amine in the ethypyrrolidine ring and the carboxylate of Aspartic Acid3.32. By keeping the ethylpyrrolidinemethyl moiety and replacing the phenyl group of eticlopride with the carborane, we prepared the first boron-containing analog of eticlopride. Our docking studies showed that carborane-containing eticlopride analog fits well within the orthosteric site. The biological tests showed that carborane analog displays improved selectivity towards the D3R as compared to eticlopride. | |
