NOVEL INHIBITORS OF GAMMA-AMINOBUTYRIC ACID (GABA) UPTAKE - ANTICONVULSANT ACTIONS IN RATS AND MICE

Abstract

SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and SK&F 100330A [N-(4,4-diphenyl-3-butenyl)-guvacine] represent a new series of potent, orally active inhibitors of GABA uptake. In vitro studies with synaptosome-rich (P2) fractions of rat brain indicated that these compounds were .apprx. 20 times more potent than the parent amino acids as inhibitors of [3H]GABA uptake. They did not inhibit [3H] muscimol binding at nM concentrations. These compounds evidently were also potent anticonvulsants when administered either orally or i.p. to rats. Both compounds attenuated the forelimb extensor component of bicuculline-induced convulsions, but had no effect on strychnine-induced convulsions, indicating that they were acting through a GABAergic mechanisn in vivo. Two animal models indicative of anticonvulsant efficacy in man are inhibition of maximal electroshock seizures (MES) and inhibition of pentylenetetrazole (PTZ) convulsions in either rats or mice. SK&F 89976A, SK&F 100330A and several related compounds were potent inhibitors of PTZ convulsions in rats. SK&F 100330A also inhibited MES convulsions in rats. Neither compound inhibited MES or electroshock seizure threshold in mice, and whereas both compounds inhibited the tonic phase of PTZ convulsions in .apprx. 50% of the mice tested; this inhibition was not dose-related. The rat appears to be a more suitable species for further testing of these compounds. The family of compounds represented by SK&F 89976A and SK&F 100330A may have clinically relevant anticonvulsant activity.