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

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.