Abstract

Many trioxabicyclooctanes [X(OCH ₂) ₃Cî—¸Y] at low doses administered ip produce tonic-clonic convulsions and death in mice. When X is P, Oî—»P, Sî—»P, Hî—¸C, alkyl-C, and C ₆H ₅î—¸C, the optimal Y substituent is tî—¸C ₄H ₉ among alkyl groups examined. In ortho carboxylic acid esters, the optimal X substituent is either small (potency decreases in the order Hî—¸C > CH ₃î—¸C) or large (C ₆H ₅î—¸C > nî—¸C ₄H ₉î—¸ > nî—¸C ₃H ₇î—¸C) while intermediate-sized substituents (C ₂H ₅î—¸C and iî—¸C ₃H ₇î—¸C) reduce or negate the toxic properties. Limited literature data on the toxicity of silatranes [X(OCH ₂CH ₂) ₃N] suggest that they may fit a similar pattern for the optimal X substituent (C ₆H ₅î—¸Si > Hî—¸Si > alkylî—¸Si). These findings and particularly the discontinuous sizeactivity relationships of X indicate that the ortho carboxylic acid esters include compounds that may act at two different nerve receptors: one receptor accepts Hî—¸C(OCH ₂) ₃Cî—¸Y and CH ₃î—¸C(OCH ₂) ₃Cî—¸Y, which mimic P(OCH ₂) ₃Cî—¸Y, Oî—»P(OCH ₂) ₃Cî—¸Y, Sî—»P(OCH ₂) ₃Cî—¸Y, and possibly Hî—¸Si(OCH ₂CH ₂) ₃N; the other accepts nî—¸C ₃H ₇î—¸C(OCH ₂) ₃Cî—¸Y, nî—¸C ₄H ₉î—¸C(OCH ₂) ₃Cî—¸Y, and C ₆H ₅î—¸C(OCH ₂) ₃Cî—¸Y, which may mimic C ₆H ₅î—¸Si(OCH ₂CH ₂) ₃N.