2-Hydroxy-saclofen: an improved antagonist at central and peripheral GABAB receptors.
2-hydroxy-saclofen (2-OH-S), a sulphonic analogue of baclofen, slightly increased the twitch height and reversibly antagonised the GABA- and baclofen-induced depression of twitch contractions in the guinea pig vas deferens and isolated ileum, causing a parallel dextral shift in the baclofen dose-response curve in a competitive manner (pA2 = 5.0) in the latter tissue. 2-OH-S (10-50 microM) reversibly elevated the spike height and antagonised the baclofen (8-20 microM)-induced suppression of ictal discharges in rat cortical slices superfused in Mg2+-free Krebs solution, the spike height declining to control level within 15 min of washout. The antagonism by 2-OH-S on GABAB receptor-mediated actions is selective, as 2-OH-S did not affect depressive responses to adenosine or morphine, or contractile responses to GABA (GABAA receptor-mediated), acetylcholine and carbachol in the ileum. Compared to phaclofen, 2-OH-S is a more potent competitive antagonist of GABAB receptor-mediated actions in the central and peripheral nervous system.
Kerr
D I
DI
Department of Pharmacology, University of Sydney, N.S.W., Australia.
Ong
J
J
Johnston
G A
GA
Abbenante
J
J
Prager
R H
RH
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007082:Ileum / Q000187:drug effects / Q000294:innervation* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000294:innervation* / Q000502:physiology
D011963:Receptors, GABA-A; D001418:Baclofen; C057491:2-hydroxysaclofen