Design and synthesis of a new series of 4-alkylated 3-isoxazolol GABA A antagonists.
A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL), in which the 4-position of the 3-isoxazolol ring is substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. While alkyl and benzyl substitution provided affinities and antagonist potencies comparable to those of 4-PIOL, diphenylalkyl and naphthylalkyl substitution resulted in marked increase in both affinity and potency. The 2-naphthylmethyl and the 3,3-diphenylpropyl analogues showed antagonist potencies comparable or markedly higher than that of the standard antagonist SR 95531. Molecular modeling studies exposed a large cavity in the vicinity of the 4-position of 4-PIOL, in which there seems to be additional sites for specific receptor interactions.
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100, Copenhagen, Denmark, bfr@dfh.dk
Bente
B
Frølund
Lena
L
Tagmose
Anne T
AT
Jørgensen
Uffe
U
Kristiansen
Tine B
TB
Stensbøl
Tommy
T
Liljefors
Povl
P
Krogsgaard-Larsen
D000478:Alkylation; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004594:Electrophysiology; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D007555:Isoxazoles; D008024:Ligands; D011724:Pyridazines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C049853:gabazine