Featured Paper of the Month – July 2017
Kumar, Vivek; Moritz, Amy E; Keck, Thomas M; Bonifazi, Alessandro; Ellenberger, Michael P; Sibley, Christopher D; Free, Benjamin R; Shi, Lei; Lane, Robert J; Sibley, David R; Newman, Amy Hauck
In: J Med Chem, vol. 60, no. 4, pp. 1478–1494, 2017, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking).
@article{Kumar:2017aa,
title = {Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R).},
author = {Vivek Kumar and Amy E Moritz and Thomas M Keck and Alessandro Bonifazi and Michael P Ellenberger and Christopher D Sibley and Benjamin R Free and Lei Shi and Robert J Lane and David R Sibley and Amy Hauck Newman},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28186762},
doi = {10.1021/acs.jmedchem.6b01688},
issn = {1520-4804 (Electronic); 0022-2623 (Linking)},
year = {2017},
date = {2017-02-10},
journal = {J Med Chem},
volume = {60},
number = {4},
pages = {1478--1494},
address = {Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.},
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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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.
