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In vitro and animal experiments have characterized KA 672-HCl as a potent functional antagonist of excitatory amino acid-induced convulsions and mortality. In receptor-binding studies, the compound displayed high affinities to several serotoninergic, adrenergic, and dopaminergic receptors and to the sigma receptor. The potential for short- and long-term toxicity of KA 672-HCl in rats and dogs was found to be low. Double-blind, randomized, placebo-controlled studies were undertaken in healthy volunteers ranging from 52 to 74 years of age to determine tolerability, safety, and preliminary pharmacokinetics of single and repeated doses in humans. Single doses up to 40 mg were well tolerated, with no difference in effect from placebo. At 60 mg, approximately half of the volunteers experienced a moderate drug-related orthostatic syndrome. After repeated doses of 10 or 20 mg KA 672-HCl for 14 days only minor adverse events of mild intensity were reported with no clear relation to dose or a clinically relevant difference from placebo. A mild decrease in semisupine and standing blood pressure 4 hours after administration was observed in the 20 mg group with no occurrence of orthostasis. Linear pharmacokinetics were observed after repeated doses. However, this was not the case after single-dose administration, as generally higher plasma concentrations were observed after the 20-mg dose than would have been predicted from the 10-mg data. The mean terminal phase half-life after the 20 mg dose was 11.1 hours and 13.7 hours after repeated and single doses, respectively. The safety and tolerability data support a continuation of therapeutic trials. KA 672-HCl is currently entering phase II development.