Stereochemical Studies on Medicinal Agents. V.¹ Synthesis, Configuration, and Pharmacological Activity of Pipradrol Enantiomers

Enantiomers of pipradrol were synthesized from (R)- and (S)-pipecolic acid and the probable conformation of the base was deduced through ir studies. It was determined that all of the central stimulant activity resided in (R)-pipradrol, and that both the (R) and (S) isomers possessed anticonvulsant properties. The fact that the more active enantiomers of pipradrol and amphetamine are not configurationally related suggests that the mode of action of these central stimulants may differ, and this is in agreement with recent work which has shown that (R)-pipradrol is direct acting while amphetamine and the ephedrines act by an indirect mechanism. The stereospecificity of pipradrol and the much lower steric requirements for indirect-acting, central stimulants has led to the generalization that direct action factors a higher degree of stereoselectivity than indirect action.