title: Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers.
abstract: Chemical mitochondrial uncouplers are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. These uncouplers have potential for the treatment of diseases such as obesity, Parkinson's disease, and aging. We have previously identified a novel mitochondrial protonophore, named BAM15, which stimulates mitochondrial respiration across a broad dosing range compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Herein, we report our investigations on the structure-activity relationship profile of BAM15. Our studies demonstrate the importance of the furazan, pyrazine, and aniline rings as well as pKa in maintaining its effective protonophore activity.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Kenwood
authors.affiliation: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Calderone
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Evan P
authors.initials: EP
authors.lastname: Taddeo
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Department of Medicine, University of Virginia, Charlottesville VA 22908, USA; Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA; Department of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
authors.affiliation: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: santosw@vt.edu.
authors.forename: Webster L
authors.initials: WL
authors.lastname: Santos
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014475:Uncoupling Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011719:Pyrazines; D014475:Uncoupling Agents; C000608313:furazano(3,4-b)pyrazine; D000255:Adenosine Triphosphate
keywords: Mitochondrial bioenergetics; Mitochondrial uncoupler; Protonophore; Pyrazines; Structure–activity relationships