Highly potent 5-aminotetrahydropyrazolopyridines: enantioselective dopamine D3 receptor binding, functional selectivity, and analysis of receptor-ligand interactions

Nuska Tschammer, Jan Elsner, Angela Goetz, Katharina Ehrlich, Stefan Schuster, Miriam Ruberg, Julia Kühhorn, Dawn Thompson, Jennifer Whistler, Harald Hübner, Peter Gmeiner

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Heterocyclic dopamine surrogates of types 5 and 7 were synthesized and investigated for their dopaminergic properties. The enantiomerically pure biphenylcarboxamide (S)-5a displayed an outstanding K(i) of 27 pM at the agonist-labeled D(3) receptor and significant selectivity over the D(2) subtype. Measurement of [(35)S]GTPγS incorporation in the presence of a coexpressed PTX-insensitive G(α0-1) subunit indicated highly efficient G-protein coupling. Comparison of ligand efficacy data from cAMP accumulation and [(3)H]thymidine incorporation experiments revealed that ligand biased signaling is exerted by the test compound (S)-5a. Starting from the D(3) crystal structure, a combination of homology modeling and site directed mutagenesis gave valuable insights into the binding mode and the intermolecular origins of stereospecific receptor recognition. According to these data, the superior affinity of the eutomer 5a is caused by the favorable binding energy that results from interaction between the ligand's central ammonium unit and the aspartate residue in position 3.32 of the receptor.

Original languageEnglish
Pages (from-to)2477-91
Number of pages15
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
Publication statusPublished - 14 Apr 2011

Keywords

  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Conformation
  • Pyrazoles
  • Pyridines
  • Receptors, Dopamine D3
  • Stereoisomerism
  • Substrate Specificity

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