Return to articles asapprevarticlenext investigation of novel primary and secondary pharmacophores and 3-substitution in the linking chain of a series of highly selective and bitopic dopamine d3 receptor antagonists and partial agonists

Anver Basha Shaik, Vivek Kumar, Alessandro Bonifazi, Adrian M. Guerrero, Sophie L. Cemaj, Alexandra Gadiano, Jenny Lam, Zheng Xiong Xi, Rana Rais, Barbara S. Slusher, Amy Hauck Newman

Research output: Contribution to journalArticle

Abstract

Dopamine D3 receptors (D3R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1-yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D3R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D3R binding affinity (Ki = 0.756 nM) and was 327-fold selective for D3R over D2R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- A nd S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D3R selectivity as well as drug-like features required for development as pharmacotherapeutics.

Original languageEnglish (US)
JournalJournal of medicinal chemistry
DOIs
StateAccepted/In press - Jan 1 2019

Keywords

  • Chiral resolution
  • Dopamine d3 receptor antagonist
  • Metabolic stability
  • Partial agonist
  • Pharmacokinetics
  • Phenylpiperazine
  • Vk4-116
  • Vk4-40

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Return to articles asapprevarticlenext investigation of novel primary and secondary pharmacophores and 3-substitution in the linking chain of a series of highly selective and bitopic dopamine d3 receptor antagonists and partial agonists'. Together they form a unique fingerprint.

  • Cite this