Open AccessThe Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists
Author(s) -
Francisco O. Battiti,
Sophie L. Cemaj,
Adrian M. Guerrero,
Anver Basha Shaik,
Jenny Lam,
Rana Rais,
Barbara S. Slusher,
Jeffery R. Deschamps,
Greg H. Imler,
Amy Hauck Newman,
Alessandro Bonifazi
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b00702
Subject(s) - chemistry , linker , selectivity , stereochemistry , moiety , receptor , homology modeling , lead compound , dopamine receptor d3 , chemical synthesis , combinatorial chemistry , dopamine receptor d2 , in vitro , biochemistry , enzyme , computer science , operating system , catalysis
Because of the large degree of homology among dopamine D 2 -like receptors, discovering ligands capable of discriminating between the D 2 , D 3 , and D 4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D 3 preferential agonists (+)-PD128,907 ( 1 ) and PF592,379 ( 2 ), we synthesized bitopic structures to further improve their D 3 R selectivity. We found that the (2 S ,5 S ) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D 3 R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D 3 R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.