Effects of the competitive N-methyl-D-aspartate antagonist CGP37849 and its ethylester CGP39551 on N-methyl-D-aspartate-evoked whole-cell currents incultured spinal neurones and on vestibular stimulation-induced seizures inEL mice

The competitive N-methyl-D-aspartate (NMDA) antagonist DL-2-amino-4-methyl- 5-phosphono-3-pentenoic acid (CAS 127910-31-0, 4-methyl-APPA, CGP 37849) an d its ethyl ester (CAS 127910-32-1, CGP 39551) potently block NMDA-evoked w hole-cell current on mouse spinal neurones in primary dissociated cell cult ures with IC50 (+/- SE) values of 189 +/- 9 nmol/l (CGP 37849) and 2100 +/- 220 nmol/l (CGP 39551), respectively. The compounds dose-dependently block ed vestibular stimulation-induced convulsions in EL mice, 2 h after oral ad ministration, with ED50 (95% CI) values of 135 (78-236) mu mol/kg (CGP 3784 9) and 65 (45-94) mu mol/ kg (CGP 39551). In male Swiss albino mice, perfor mance in the step-through passive avoidance procedure was dose-dependently impaired with ED50 (95% CI) values of 85 (56-157) mu mol/kg (CGP 37849) and 27 (18-42) mu mol/kg (CGP 39551). In addition performance of these animals in the rotarod test of motor coordination was impaired, 2 h after oral adm inistration of CGP 39551, with an ED50 (95% CI) of 142 (100-201) mu mol/kg. These findings demonstrate anticonvulsant activity in these potent NMDA an tagonists after oral administration with CGP 39551 possessing greater relat ive potency. However, the unfavourable ratio of therapeutic dose versus dos e inducing memory or motor impairment supports the prevailing notion that s uch adverse effects of the presently available compounds preclude the use o f NMDA antagonists as long-term therapies.