新睡眠薬及び睡眠薬拮抗物質の探索研究から睡眠機構研究に辿りつくまで —バルビツール酸からウリジンまで（その1)<sup>1)</sup>—

Abstract

Thirty-six allyl substituted oxopyrimidine analogues such as barbituric acid (BA), barbiturates, uracil, thymine, and related derivatives including 13 new compounds were synthesized and their pharmacologic effects ([hypnotic activity, anticonvulsant activity against pentylentetrazol (PTZ)-induced seizures, and LD(50)]) and interactions with the barbiturates were evaluated in mice and rats. The results are briefly and parially summarized as follows. BA prolonged pentobarbital (PB)-induced sleep and had some central depressant effects. N,5,5-triallyl-BA exhibited some hypnotic and anticonvulsant activities, although the other 5,N-allyl-compounds did not show any activity except for allobarbital (AlloB). N-allyl-BA, 5-allyl-BA, N(1),N(3),5-triallyl-BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA also prolonged PB-induced sleep. Interestingly, N,5,5-triallyl-BA was the most potent in the interaction with AlloB, phenobarbital (PheB), amobarbital (AB), PB, and thiopental (TP) but not barbital (B). N(1),N(3),5,5-tetraallyl-BA prolonged AlloB-, PB-, and AB-induced sleep but not B-, PheB-, and TP-induced sleep. N(1),N(3),5-triallyl-B prolonged only PB- and TP-induced sleep. 5,5-diallyl-BA prolonged PheB- and TP-induced sleep. N,5-diallyl-BA prolonged only TP-induced sleep. In contrast, BA and N(1),N(3),5-triallyl-AB tended to antagonize AlloB, AB, and B. N(1),N(3),5,5-tetraallyl-BA also slightly antagonized B, PheB, and TP. 5,5-diallyl-BA antagonized only AB. The prolonging effects of BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA on PB-induced sleep were dose dependent. These results indicate that the position and number of allyl groups substituted on the structure of BA play an important role in their depressant activities. This review deals with the structure-activity relationship of allyl-substituted oxopyrimidines as part of our search for antagonists and agonists of barbiturates as well as their mechanisms of action.