title: Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3Receptor (D3R).
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 D3receptor (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.
authors.affiliation: 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.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , 35 Convent Drive, MSC-3723, Bethesda, Maryland 20892-3723, United States.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Moritz
authors.affiliation: 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.
authors.forename: Thomas M
authors.identifier: 0000-0003-1845-9373
authors.initials: TM
authors.lastname: Keck
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: 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.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Ellenberger
authors.affiliation: 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.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Sibley
authors.affiliation: Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , 35 Convent Drive, MSC-3723, Bethesda, Maryland 20892-3723, United States.
authors.forename: R Benjamin
authors.initials: RB
authors.lastname: Free
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 399 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.affiliation: Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , 35 Convent Drive, MSC-3723, Bethesda, Maryland 20892-3723, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.affiliation: 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.
authors.forename: Amy Hauck
authors.identifier: 0000-0001-9065-4072
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D011869:Radioligand Assay; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C553924:1H-indole-2-carboxylic acid (4-(2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)cyclohexyl)amide; D003521:Cyclopropanes; D018492:Dopamine Antagonists; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D050637:Receptors, Dopamine D3