Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D4 Receptor Agonists with High Subtype Selectivity

J Med Chem. 2019 Nov 14;62(21):9658-9679. doi: 10.1021/acs.jmedchem.9b01085. Epub 2019 Oct 30.

Abstract

Many subtype-selective dopamine receptor ligands developed for the D2-D4 family incorporate a 1-arylpiperazine-derived primary recognition motif, which is connected to a lipophilic moiety occupying an extended binding pocket (EBP) of the receptor via an aliphatic linker of variable lengths. The evaluation of a novel group of dopamine receptor ligands now showed that highly subtype-selective ligands [up to Ki(D4.4) = 0.25 nM, D2L/D4.4 = 320, D3/D4.4 = 710 for APH199 (17)] can be obtained by choosing a relatively large and conformationally flexible 1-benzyl-1-phenylsemicarbazide substructure to fill the EBP. The novel chemotype APH199 (17) was found to act as a full agonist at the D4 receptor showing significant bias toward G protein activation over β-arrestin recruitment in comparison to quinpirole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dopamine Agonists / chemistry*
  • Dopamine Agonists / pharmacology*
  • Drug Design*
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Receptors, Dopamine D4 / chemistry
  • Receptors, Dopamine D4 / metabolism*
  • Substrate Specificity
  • Thiosemicarbazones / chemistry*
  • Thiosemicarbazones / pharmacology*

Substances

  • Dopamine Agonists
  • Thiosemicarbazones
  • Receptors, Dopamine D4
  • GTP-Binding Proteins