Effects of para-substitution on tissue levels and alpha-adrenoceptor antagonist properties of tolazoline.

Tolazoline and a series of para-substituted analogues were examined in mice to determine the effects of para substitution on alpha-adrenoceptor antagonist potency and tissue disposition. alpha-Adrenoceptor antagonism was measured as abilities to attenuate the hypothermic or sedative actions of clonidine. In general, para substitution by electron-withdrawing metabolically stable groups (Cl, F) resulted in increased or unchanged brain levels of drug relative to tolazoline. The para substitution by electron-donating metabolically labile groups (CH3, OCH3) leads to reduced brain levels. Effects on alpha-adrenoceptor antagonist properties did not follow a similar pattern. Thus, increased or decreased antagonism of clonidine effects by para-chloro- or para-methyl-tolazoline, respectively, could be attributed solely to increased or decreased brain levels of drug. para-Fluorotolazoline did not antagonize clonidine but was present in brain at levels equivalent to those of tolazoline. para-Methoxytolazoline on the other hand could not be detected in any tissue but antagonised hypothermia more readily than sedation. These data indicate that the factors governing the disposition or alpha-adrenoceptor antagonist properties of tolazoline analogues are different and independent of each other.