The effects of
alaproclate and
GEA-857 (2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate) on the production of
cyclic GMP in the rat cerebellum in vivo induced by stimulation of
N-methyl-D-aspartate (
NMDA) receptors were studied.
Alaproclate per se at a dose of 20 mg/kg subcutaneously, did not influence the basal cGMP level. The increase in cGMP induced by
harmaline (20 mg/kg subcutaneously) was dose-dependently antagonized by
alaproclate (5-40 mg/kg subcutaneously). S-(-)-
Alaproclate was 2-5 times more potent than the R-(+)-enantiomer.
GEA-857 which in contrast to
alaproclate is a very weak
5-HT uptake inhibitor shared the ability of
alaproclate to inhibit the effect of
harmaline on cGMP accumulation with similar potency to S-(-)-
alaproclate.
Alaproclate at 15 mg/kg subcutaneously blocked the increase in cGMP in cerebellum caused by
NMDA itself at 200 mg/kg subcutaneously. In contrast to
alaproclate, the K+ channel antagonist,
4-aminopyridine, 5 mg/kg subcutaneously, produced per se an increase in cGMP levels in the rat cerebellum by 300% which was antagonized by the
NMDA receptor antagonists,
dizocilpine,
phencyclidine and (+/-)-CCP, the
nitric oxide synthase inhibitor,
NG-nitro-L-arginine methyl ester and by
alaproclate.
Alaproclate.
Alaproclate and
GEA-857 antagonized
seizures induced by
NMDA, 200 mg/kg subcutaneously at doses similar to those antagonizing the
harmaline- and
NMDA-induced elevation of cerebellar cGMP. Neither
alaproclate nor
GEA-857 caused any behavioural effects typical for uncompetitive
NMDA receptor antagonists except a slight increase in motor activity and sniffing. The effect of
alaproclate on the
NMDA receptor-mediated increase in cGMP in rat cerebellum in vivo might be due to blockade of the
cation channel of the
NMDA receptor complex previously observed in in vitro experiments and these compounds seems to belong to the group of low-affinity uncompetitive
NMDA receptor antagonists that might have clinical interest.