Cook C E, Seltzman T P, Tallent C R, Wooten J D
J Pharmacol Exp Ther. 1982 Mar;220(3):568-73.
Although it has been demonstrated that immunization with drug-protein conjugates derived from enantiomerically pure drug derivatives leads to stereoselective antisera, the effect of the use of conjugates of racemic drugs on antibody stereoselectivity has received little attention. Antisera were developed by immunizing rabbits with a conjugate (1) of the hemisuccinate of the antimalarial drug 1-(1,3-dichloro-6-trifluoromethyl-9-phenanthryl)-3-N, N-dibutylaminopropan-1-ol (WR 171,669) and bovine thyroglobulin. These antisera in binding competition studies with tritium-labeled racemic WR 171,669 demonstrated different stereoselective for d-, l- and dl-WR 171-669. Immunization with a conjugate (II) made from a nonchiral analog of the drug led to antisera which showed little discrimination between the optical isomers. Hydrolysis of conjugate I showed no excess of one enantiomer over the other, thus indicating that the stereoselectivity was the result of stereoslective processing of the conjugate by the immune system. The use of antisera from racemic conjugates to analyze total drug levels must be examined in each case ot avoid errors. The use of conjugate achiral drug analogs leading to the production of antisera relatively "blind" to enantiomeric differences is one solution to the problem of selective antisera.
尽管已经证明，用源自对映体纯药物衍生物的药物 - 蛋白质缀合物进行免疫可产生立体选择性抗血清，但外消旋药物缀合物的使用对抗体立体选择性的影响却很少受到关注。通过用抗疟药物1-(1,3 - 二氯 - 6 - 三氟甲基 - 9 - 菲基)-3 - N，N - 二丁基氨基丙 - 1 - 醇（WR 171,669）的半琥珀酸酯与牛甲状腺球蛋白的缀合物（1）免疫兔子来制备抗血清。在与氚标记的外消旋WR 171,669的结合竞争研究中，这些抗血清对d -、l - 和dl - WR 171 - 669表现出不同的立体选择性。用由该药物的非手性类似物制成的缀合物（II）进行免疫产生的抗血清，对光学异构体几乎没有区分能力。缀合物I的水解显示一种对映体相对于另一种没有过量，因此表明立体选择性是免疫系统对缀合物进行立体选择性加工的结果。在每种情况下都必须检查使用来自外消旋缀合物的抗血清来分析总药物水平，以避免误差。使用导致产生对映体差异相对“盲目”的抗血清的非手性药物类似物缀合物是解决选择性抗血清问题的一种方法。
