Anticonvulsant actions of DS 103-282. Pharmacological studies in rodents and the baboon, Papio papio

The anticonvulsant actions of DS 103-282 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3- benzothiadazole , tizanidine], have been evaluated after intraperitoneal administration in DBA/2 mice (seizures induced by sound), in Swiss S mice (seizures induced by N-methyl-D,L-aspartate; NMDLA ) and following intravenous or oral administration in Papio papio (seizure responses to intermittent photic stimulation). Protection against sound-induced seizures occurred after intraperitoneal administration of DS 103-282 (0.66-3.33 mg/kg). The ED50 doses for suppression of the tonic, clonic and wild-running phases of sound-induced seizures were 0.53, 0.79 and 1.3 mg/kg respectively. This protective effect of DS 103-282 (1.5 mg/kg, i.p.) was maximal after 30 min and was maintained for 60-120 min. Seizures induced by NMDLA were not suppressed by DS 103-282 (3.3-10 mg/kg, i.p.). In the baboons, a transient protection against photomyoclonic responses was observed 1 hr after intravenous administration of DS 103-282 (2-4 mg/kg). A similar profile of action was seen after oral administration of larger doses of DS 103-282 (16-32 mg/kg). Unwanted effects of DS 103-282 included transient piloerection, slight disturbance of gait and a fall in rectal temperature in mice, and muscular hypotonia and signs of sedation in baboons. These studies demonstrate an anticonvulsant action of DS 103-282, in both rodent and primate models of epilepsy, but do not support a postsynaptic blockade in excitatory neurotransmission as the mechanism of this action.