GABAA agonists: resolution and pharmacology of (+)- and (-)-isoguvacine oxide.
(3SR,4RS)-3,4-Epoxypiperidine-4-carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)-1-(benzyl-oxycarbonyl)-3,4-epoxypiperidin e-4-carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee > or = 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 microM), (+)-isoguvacine oxide (IC50 = 0.20 +/- 0.03 microM) and (-)-isoguvacine oxide (IC50 = 0.32 +/- 0.05 microM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)-isoguvacine oxide (EC50 = 6 microM; 33% relative efficacy) and (-)-isoguvacine oxide (EC50 = 5 microM; 38% efficacy relative to 10 microM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor-associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure-activity studies on GABAA agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Frølund
B
B
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Jeppesen
L
L
Krogsgaard-Larsen
P
P
Hansen
J J
JJ
D000818:Animals; D018755:GABA Agonists / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D066298:In Vitro Techniques; D010875:Pipecolic Acids / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA; D011963:Receptors, GABA-A / Q000378:metabolism; D013237:Stereoisomerism
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D010875:Pipecolic Acids; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C030802:isoguvacine oxide