Anti-stress activity of N-phthaloyl gamma-aminobutyric acid in rats.

The effect of immobilization restraint stress (RS) on some biochemical and biophysical parameters in rats and their modulation by N-phthaloyl gamma-aminobutyric acid (P.GABA) was studied. RS did not affect the levels of serum Ca2+, inorganic phosphate, bilirubin, total protein, but caused insignificant increase of albumin level and significantly decreased the cholesterol level. This RS induced decrease of serum cholesterol level was reversed by prior treatment with P.GABA, while the albumin content showed a decrease. RS-induced a generalised increase in serum enzyme activity of lactate dehydrogenase (LDH), alkaline phsophatase (AIP), serum glutamate pyruvate transaminase (SGPT) and serum glutamate-oxaloacetate transaminase (SGOT). P.GABA normalised RS-induced increase of LDH and AlP activity, but it further enhanced SGOT and SGPT activities. In synaptosomal membranes, RS caused a decrease in clusterization and fluidity, but the thickness of the membrane increased as studied by fluorescence probes. Prior administration of P.GABA normalised the changes observed in the synaptic membrane.

Antinociceptive action of N-octanoyl GABA--a new GABA mimetic agent.

A new derivative of gamma-aminobutyric acid (GABA) was synthesized. The compound, N-octanoyl GABA (O-GABA), exhibited positive analgesic response in four different models in mice--tail immersion, hot plate, tail clip and acetic acid induced writhing. The antinociceptive activity was significantly blocked by picrotoxin but not by bicuculline or 3-mercaptopropionic acid. Naloxone failed to reverse the antinociceptive response of O-GABA but a synergistic action was observed with pethidine. Pretreatment with atropine significantly reduced the antinociceptive action of O-GABA. Biochemical tests revealed that O-GABA significantly increased brain GABA levels.

Effect of GABA analogues on various components of maximum electroshock-induced seizures in mice.

Out of fourteen compounds reported here only four [N-valproyl GABA (V.GABA), N-phthaloyl GABA (P.GABA), gamma-phthalimido N-amyl butyramide (PGA) and gamma-phthalimido N-phenyl butyramide (PGP)] gave significant protection to all the four components of maximal electroshock-induced seizures (MES) in mice. It appeared that substitution of either amino or carboxylic or both groups of gamma-aminobutyric acid (GABA) with bulkier groups like aliphatic or aromatic carbons usually produced effective anticonvulsant GABA derivatives. V.GABA and P.GABA were the most effective anticonvulsant GABA derivatives in protecting all the components of MES-induced seizures. They were 2.3 and 1.5 times potent than sodium valproate in molar ratio, but P.GABA has low therapeutic index when compared to V.GABA. The observed anticonvulsant activity may be due to enhanced GABA concentration in the CNS. Probably, the active compound (V.GABA) crossed the blood brain barrier and hydrolysed to GABA and valproic acid to bring about its anticonvulsant action.

Neuropharmacology of amide derivatives of P-GABA.

Three lipophilic amide derivatives of phthaloyl-GABA (P-GABA), namely gamma-phthalimido N-amyl butyramide (PGA), gamma-phthalimido-N-hexylbutyramide (PGH) and gamma-phthalimido N-phenylbutyramide (PGP), were synthesized and evaluated for their hypnotic and anticonvulsant activities in mice. Both PGA and PGH showed moderate hypnotic activity but PGP had no such action. Picrotoxin (0.08 mg/kg) a non-specific GABA antagonist completely abolished the hypnotic action of PGA in subconvulsive doses. Bicuculline (0.04 mg/kg) a GABAA antagonist, 3-mercaptopropionic acid (6 mg/kg) a GAD inhibitor at subconvulsive doses failed to neutralise the hypnotic action of PGA. On the other hand, PGA showed significant protection only against picrotoxin-induced convulsions, but was inactive against other convulsants tested. PGP which has no hypnotic activity, and has a mild anticonvulsant action in all the models except picrotoxin. A definite correlation was observed between the brain GABA and the hypnotic activity of PGA. However the present data indicate that the hypnotic and anticonvulsant activities are mediated probably through different brain GABA-ergic mechanisms.