Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D 3 Receptor (D 3 R)

The development of bitopic ligands directed toward D -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 D receptor (D R)-selective m...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-02, Vol.60 (4), p.1478-1494
Main Authors: Kumar, Vivek, Moritz, Amy E, Keck, Thomas M, Bonifazi, Alessandro, Ellenberger, Michael P, Sibley, Christopher D, Free, R Benjamin, Shi, Lei, Lane, J Robert, Sibley, David R, Newman, Amy Hauck
Format: Article
Language:English
Subjects:
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
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Summary:The development of bitopic ligands directed toward D -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 D receptor (D R)-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 D R-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 D R-selective antagonists, 18a and 25a, which further delineates SAR associated with allosterism at D R and provides leads toward novel drug development.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01688