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Novel bivalent ligands based on the sumanirole pharmacophore reveal dopamine D2 receptor (D2R) biased agonism and allosteric modulation

Wednesday, September 13, 2017 — Poster Session I

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • A Bonifazi
  • H Yano
  • AM Guerrero
  • L Muller
  • A Woods
  • L Shi
  • G Tanda
  • AH Newman


Several neuropsychiatric disorders have been associated with hypo- or hyper-activation of specific dopamine transmission pathways involving the D2R subtypes. Sumanirole, originally developed for the treatment of Parkinson’s disease and restless legs syndrome, is a full orthosteric agonist showing moderately high D2R affinity and modest D2R selectivity. Despite the failure in clinical trials, sumanirole has served as a valuable template for lead optimization and structure-activity relationship (SAR) studies. G-protein coupled receptors (GPCRs), of which D2R is a member, can adopt several biologically active conformations stabilized by ligands interacting with spatially distinct binding sites. In this study, a novel series of selective D2 ligands has been designed and synthesized linking sumanirole or N-propyl substituted sumanirole pharmacophores with several secondary molecular fragments inspired by known small molecules. The resulting bivalent ligands were designed to explore the molecular requirements of the secondary binding pocket and thereby achieve improved D2R affinity, selectivity, and further biased and allosteric properties. All newly synthesized compounds were evaluated in radioligand competition binding assays, as well as in 5 different functional BRET (bioluminescence energy transfer) assays. We have identified novel full agonists with highly selective D2R G-protein bias profiles as well as promising potential allosteric modulators. To further validate the experimentally observed G-protein functional selectivity of the new lead molecules, two independent mathematical models were used to calculate bias factor parameters. Moreover, additional in vivo studies are currently underway in an attempt to relate the activation and/or blockade of specific signaling pathways with their consequent behavioral effects.

Category: Chemical Biology