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Amidines Amidines Q 0500Novel N 1 -(Benzyl)cinnamamidine Derived NR2B Subtype-Selective NMDA Receptor Antagonists. -The synthesis of title compounds such as (V) and (X) by reaction of cinnamimidate (III) with the appropriate amine or via Horner-Wadsworth-Emmons reaction of an amidine phosphonate and their evaluation as NR2B subtype NMDA receptor ligands are described. Compound (Vb) showed excellent selectivity over NR2A (no yields given). -(CURTIS*, N. R.; DIGGLE, H. J.; KULAGOWSKI, J. J.; LONDON, C.; GRIMWOOD, S.; HUTSON, P. H.; MURRAY, F.; RICHARDS, P.; MACAULAY, A.; WAFFORD KEITH A.; Bioorg. Med. Chem. Lett. 13 (2003) 4, 693-696; Merck Sharp Dohme Res. Lab., Dep. Med. Chem., Neurosci. Res. Cent., Harlow, Essex CM20 2QR, UK; Eng.) -M. Schroeter 25-110

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Both aspirin at a high dose (400 mg kg-l) and caffeine (5 mg kg-') induced hyperactivity in the DA rat, but lower doses of aspirin were without effect. Caffeine-induced hyperactivity was brief (2 h) but that due to aspirin was evident fiom 1-6 h after dosing. Co-administration of the two drugs caused long-lasting hyperactivity, even with doses of aspirin which had no

The interactive effects of caffeine and phenacetin on the locomotor activity of the DA rat involved changes in absorption and metabolism as well as effects possibly exerted at the cns level. Phenacetin initially retarded the absorption of caffeine when coadministered by gavage but not when caffeine was given intraperitoneally and phenacetin orally. Phenacetin also increased the time for the plasma/caffeine concentration to peak, increased its peak concentration and prolonged its presence in the plasma. Urinary excretion patterns, suggested a blockade of the N‐demethylation of caffeine by phenacetin. In contrast, caffeine had only a minor influence on the absorption and metabolism of phenacetin. The locomotor effects of the caffeine‐phenacetin combination reflected the absorptive and metabolic interactions which occurred. Caffeine‐induced hyperactivity was initially masked by phenacetin in a dose‐dependent manner but after 2 h, when the plasma phenacetin concentrations were much lower, its retarding influence on caffeine metabolism became apparent and hyperactivity consequent upon an elevated plasma caffeine concentration was seen. Phenacetin also antagonized the hyperactive effects of theophylline and of (+)‐amphetamine.