Fluoro-substituted phenylazocarboxamides: Dopaminergic behavior and N-arylating properties for irreversible binding

Bioorg Med Chem. 2015 Jul 15;23(14):3938-47. doi: 10.1016/j.bmc.2014.12.012. Epub 2014 Dec 17.

Abstract

Phenylazocarboxamides can serve as bioisosteres for cinnamides, which are widely occurring substructures in medicinal chemistry. Starting from our lead compound 2, the introduction of additional fluoro substituents and the exchange of the methoxyphenylpiperazine head group by an aminoindane moiety was investigated resulting in dopamine D3 receptor antagonists and agonists with Ki values in the sub- and low-nanomolar range. As a potentially irreversible ligand, the 3,4,5-trifluoro-substituted phenylazocarboxamide 7 was investigated for its N-arylating properties by incubation with the protected lysine analog 18 and with the L89K mutant of the dopamine D3 receptor. Whereas covalent bond formation with the lysine unit in TM2 of D3 could not be detected, substantial N-arylation of the side chain of the model compound 18 has been observed.

Keywords: Azocarboxamide; Bioisosteres; Covalent ligands; D(3) receptor; Dopamine; GPCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • Fluorine / chemistry
  • Glutamic Acid / chemistry
  • HEK293 Cells / drug effects
  • Humans
  • Ligands
  • Lysine / chemistry
  • Molecular Structure
  • Mutation
  • Receptors, Dopamine D3 / agonists*
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship*

Substances

  • Amides
  • Ligands
  • Receptors, Dopamine D3
  • Fluorine
  • Glutamic Acid
  • Lysine