Danielson T J
Can J Physiol Pharmacol. 1986 Jul;64(7):1027-31. doi: 10.1139/y86-175.
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.
在小鼠中检测了妥拉唑啉及其一系列对位取代类似物，以确定对位取代对α-肾上腺素能受体拮抗剂效力和组织分布的影响。通过减弱可乐定的降温或镇静作用的能力来测定α-肾上腺素能受体拮抗作用。一般来说，相对于妥拉唑啉，用吸电子的代谢稳定基团（Cl、F）进行对位取代会导致药物在脑内的水平升高或不变。用供电子的代谢不稳定基团（CH3、OCH3）进行对位取代会导致脑内水平降低。对α-肾上腺素能受体拮抗剂特性的影响并不遵循类似模式。因此，分别用对氯-或对甲基-妥拉唑啉增强或减弱可乐定作用的拮抗作用，可能仅仅归因于药物在脑内水平的升高或降低。对氟妥拉唑啉不拮抗可乐定，但在脑内的水平与妥拉唑啉相当。另一方面，在任何组织中都检测不到对甲氧基妥拉唑啉，但它比镇静作用更易拮抗体温过低。这些数据表明，控制妥拉唑啉类似物分布或α-肾上腺素能受体拮抗剂特性的因素是不同的，且相互独立。
