Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid(A) receptor ligands: synthesis, pharmacology, and structure-activity relationships.
A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.
Møller
Henriette A
HA
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK 2100 Copenhagen.
Sander
Tommy
T
Kristensen
Jesper L
JL
Nielsen
Birgitte
B
Krall
Jacob
J
Bergmann
Marianne L
ML
Christiansen
Bolette
B
Balle
Thomas
T
Jensen
Anders A
AA
Frølund
Bente
B
D000818:Animals; D002460:Cell Line; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058805:GABA Uptake Inhibitors; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000187:drug effects / Q000502:physiology
D018756:GABA Antagonists; D058805:GABA Uptake Inhibitors; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D011963:Receptors, GABA-A