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

Vivek Kumar, Amy E. Moritz, Thomas M. Keck, Alessandro Bonifazi, Michael P. Ellenberger, Christopher D. Sibley, R. Benjamin Free, Lei Shi, J. Robert Lane, David R. Sibley, Amy Hauck Newman

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32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1478-1494
Number of pages17
JournalJournal of Medicinal Chemistry
Volume60
Issue number4
DOIs
StatePublished - Feb 23 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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