Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R)

J Med Chem. 2017 Feb 23;60(4):1478-1494. doi: 10.1021/acs.jmedchem.6b01688. Epub 2017 Feb 10.

Abstract

The development of bitopic ligands directed toward D2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a trans-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D3R-selective antagonists, 18a and 25a, which further delineates SAR associated with allosterism at D3R and provides leads toward novel drug development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Cyclopropanes / chemistry*
  • Cyclopropanes / pharmacology*
  • Dopamine Antagonists / chemistry*
  • Dopamine Antagonists / pharmacology*
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Ligands
  • Radioligand Assay
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship

Substances

  • 1H-indole-2-carboxylic acid (4-(2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)cyclohexyl)amide
  • Cyclopropanes
  • Dopamine Antagonists
  • Indoles
  • Isoquinolines
  • Ligands
  • Receptors, Dopamine D3