Central Nervous System of Some 2-Pyridyl Compounds. ∗

Abstract

In studies employing our previously described technics used in screening drugs for anti-convulsant activity( 1 ), a variety of chemical structures containing a 2-substituted pyridine grouping have been investigated (Table I). Several piperidine and quinoline compounds of similar configuration have been examined for comparative purposes. The syntheses of a large majority of these compounds have been described recently by Boekelheide and Agnello( 2 ).† The pharmacological actions of previously studied pyridine derivatives have been reviewed by Von Oettinger( 3 ). More recently Fromherz and Spiegelberg( 4 , 5 ) have investigated a series of 3-substituted pyridine compounds from a pharmacodynamic viewpoint, and Valenzuela and Huidobro( 6 ) have studied the effects of some similar compounds upon neuromuscular transmission. No studies of the presently considered 2-substituted pyridine compounds relating to central nervous action have been described.

Experimental. Table I shows the dose of the various compounds administered to mice required to paralyze half the animals (ED₅₀, loss of righting reflex). Also shown are the doses required to protect half the mice against the tonic phase of maximal electrical seizure pattern induced by a shock of 8 milliamperes of current applied for 0.5 second through ear electrodes. The ratios of these doses to the median lethal dose are given also for each compound. In most instances, several groups of 5 or 10 mice each were used to determine each value shown. The various dosages shown in Table I were obtained together with their standard errors where shown, by the plotting procedure of Miller and Tainter( 7 ).

These compounds showed no significant protection against strychnine or metrazol convulsions in experiments in which 2 lethal doses of the convulsant were injected into mice intraperitoneally 5 minutes after the intraperitoneal administration of the compound to be tested. Survivals at the end of one hour were counted and a mean protecting dose, if any, was calculated.