PHARMACOLOGICAL EFFECTS OF THE NONCOMPETITIVE NMDA ANTAGONIST CNS-1102 IN NORMAL VOLUNTEERS

1 Non-competitive antagonists at the glutamatergic N-methyl D-aspartat e receptor significantly reduce the volume of ischaemic cerebral infar ction in animals and are potential agents for the treatment of acute s troke in humans. 2 CNS 1102, a novel non-competitive NMDA antagonist, was administered as a 15 min intravenous infusion to healthy male volu nteers in a double-blind, placebo-controlled, dose-ranging study. This was the first administration to man. 3 Clinically significant sedatio n, increased mean arterial pressure and pulse rate were seen at doses of 30 mu g kg(-1) and above. Symptoms of sedation and central nervous excitation became unacceptable for conscious individuals at doses of 4 5 mu g kg(-1) and above. 4 Rapid onset of central nervous system effec ts after administration is in keeping with rapid distribution of CNS 1 102 to brain. Steady state volume of distribution was large (444 1) an d terminal elimination half-life from plasma was approximately 4 h. 5 Pharmacokinetic properties are favourable for a potential neuroprotect ive therapy. The maximum tolerated dose for conscious individuals was 30 mu g kg(-1) given intravenously over 15 min. Further assessment of CNS 1102 should seek methods of drug administration which maximise adm inistered dose with minimal side effects.