Functionally selective dopamine D2/D3 receptor agonists comprising an enyne moiety

J Med Chem. 2013 Jun 27;56(12):5130-41. doi: 10.1021/jm400520c. Epub 2013 Jun 17.


Dopaminergics of types 1 and 2 incorporating a conjugated enyne as an atypical catechol-simulating moiety were synthesized in enantiomerically pure form and investigated for their metabolic stability. Radioligand binding studies indicated high affinity to D2-like receptors. The test compounds were evaluated for their ability to differentially activate distinct signaling pathways. Measurement of D(2L)- and D(2S)-mediated [(35)S]GTPγS incorporation in the presence of coexpressed Gα(o) and Gα(i) subunits showed significantly biased receptor activation for several test compounds. Thus, the 2-azaindolylcarboxamide (S)-2a exhibited substantial functional selectivity for D(2S)-promoted G(o) activation over G(i) coupling. The most significant bias was determined for the triazolylalkoxy-substituted benzamide (S)-2c that displayed higher potency for G(o) activation than for G(i) coupling at the D(2L) subtype. Functional selectivity for β-arrestin recruitment over G(i) activation was observed for the biphenylcarboxamide (R)-1 and the 2-benzothiophenylcarboxamide (S)-2d, whereas the 2-substituted azaindole (S)-2a preferred β-arrestin recruitment compared to G(o) coupling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemistry*
  • Alkynes / chemistry*
  • Alkynes / metabolism
  • Alkynes / pharmacology*
  • Animals
  • Dopamine Agonists / chemistry*
  • Dopamine Agonists / metabolism
  • Dopamine Agonists / pharmacology*
  • Drug Stability
  • Humans
  • Ligands
  • Male
  • Models, Molecular
  • Protein Conformation
  • Rats
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D3 / agonists*
  • Receptors, Dopamine D3 / chemistry
  • Stereoisomerism
  • Substrate Specificity


  • Alkenes
  • Alkynes
  • Dopamine Agonists
  • Ligands
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3