The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists

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

Research output: Contribution to journalArticle

Abstract

Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 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 D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. 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 D3R 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.

Original languageEnglish (US)
Pages (from-to)6287-6314
Number of pages28
JournalJournal of medicinal chemistry
Volume62
Issue number13
DOIs
StatePublished - Jun 19 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Battiti, F. O., Cemaj, S. L., Guerrero, A. M., Shaik, A. B., Lam, J., Rais, R., Slusher, B. S., Deschamps, J. R., Imler, G. H., Newman, A. H., & Bonifazi, A. (2019). The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists. Journal of medicinal chemistry, 62(13), 6287-6314. https://doi.org/10.1021/acs.jmedchem.9b00702