title: Evaluation of difluoromethyl ketones as agonists of the γ-aminobutyric acid type B (GABAB) receptor.
abstract: The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABAB agonists that are not structurally analogous to known GABAB agonists, such as baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl ketones were assembled in three synthetic steps using a trifluoroacetate-release aldol reaction. Following evaluation at clinically relevant GABA receptors, we have identified a difluoromethyl ketone that is a potent GABAB agonist, obtained its X-ray structure, and presented preliminary in vivo data in alcohol-preferring mice. The behavioral studies in mice demonstrated that this compound tended to reduce the acoustic startle response, which is consistent with an anxiolytic profile. Structure-activity investigations determined that replacing the fluorines of the difluoromethyl ketone with hydrogens resulted in an inactive analogue. Resolution of the individual enantiomers of the difluoromethyl ketone provided a compound with full biological activity at concentrations less than an order of magnitude greater than the pharmaceutical, baclofen.
authors: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
authors: Changho
authors: C
authors: Han
authors: Amy E
authors: AE
authors: Salyer
authors: Eun Hoo
authors: EH
authors: Kim
authors: Xinyi
authors: X
authors: Jiang
authors: Rachel E
authors: RE
authors: Jarrard
authors: Matthew S
authors: MS
authors: Powers
authors: Aaron M
authors: AM
authors: Kirchhoff
authors: Tolani K
authors: TK
authors: Salvador
authors: Julia A
authors: JA
authors: Chester
authors: Gregory H
authors: GH
authors: Hockerman
authors: David A
authors: DA
authors: Colby
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D058786:GABA-B Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D018080:Receptors, GABA-B / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058786:GABA-B Receptor Agonists; D007659:Ketones; D018080:Receptors, GABA-B