title: Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acid(a) receptor agonists.
abstract: A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA(A) receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. The unsubstituted 4-AHP analogue (2a) (EC(50) 19 μM, R(max) 69%) was a moderately potent agonist at human α(1)β(2)γ(2) GABA(A) receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α(1)β(2)γ(2) GABA(A) receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP, 1). Selectivity for α(1)β(2)γ(2) over ρ(1) GABA(A) receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Jette G
authors.initials: JG
authors.lastname: Petersen
authors.forename: Rikke
authors.initials: R
authors.lastname: Bergmann
authors.forename: Henriette A
authors.initials: HA
authors.lastname: Møller
authors.forename: Charlotte G
authors.initials: CG
authors.lastname: Jørgensen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Jesper
authors.initials: J
authors.lastname: Kristensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Uffe
authors.initials: U
authors.lastname: Kristiansen
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D003198:Computer Simulation; D058785:GABA-A Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009118:Muscimol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D058785:GABA-A Receptor Agonists; D009118:Muscimol