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 gamma-aminobutyric acid (GABA) uptake. In vitro studies with synaptosome-rich (P2) fractions of rat brain indicated that these compounds were approximately 20 times more potent than the parent amino acids as inhibitors of [3H]GABA uptake. They did not inhibit [3H] muscimol binding at nanomolar concentrations. The present studies demonstrated that these compounds 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 mechanism in vivo. Two animal models which are known to be indicative of anticonvulsant efficacy in man are inhibition of maximal electroshock seizures (MES) and inhibition of pentylenetetrazol (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. In contrast, neither compound inhibited MES or electroshock seizure threshold in mice, and whereas both compounds inhibited the tonic phase of PTZ convulsions in approximately 50% of the mice tested, this inhibition was not dose-related. Thus, the rat appears to be a more suitable species for further testing of these compounds. These studies indicate that the family of compounds represented by SK&F 89976A and SK&F 100330A may have clinically relevant anticonvulsant activity.