De Jong A P, Soudijn W
Eur J Pharmacol. 1981 Jan 16;69(2):175-88. doi: 10.1016/0014-2999(81)90412-x.
The inhibition of specific [3H]clonidine binding to alpha-adrenergic receptors in rat brain has been studied for 43 compounds structurally related to clonidine. Oxymetazoline was found to be the most potent compound in displacing [3H]clonidine from its binding sites. 2-Methylimidazoline, 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline and heterocyclic N-methyl-substituted compounds showed no affinity at all for [3H]clonidine receptor sites. There was a good correlation between hypotensive activity and alpha 2-adrenergic receptor affinity to some 2-(phenylamino)imidazolidines. Parallelisms between Ki's and pharmacological activities were also observed for other compounds. Apparent structural requirements for alpha 2-receptor affinity were the presence of an aromatic moiety and a N-hydrogen in the heterocyclic ring. Ortho substitution in the phenyl ring was necessary for high affinity. Compounds with an oxazolidine ring had approximately similar affinities for the [3H]clonidine binding sites compared with the corresponding imidazolines (except for the 2,6-dichlorophenyl-substituted compound) whereas the pyrrolidine derivatives showed a 10-fold weaker affinity. [3H]Clonidine sites showed a homogeneous character. KD values from saturation and displacement experiments were in good agreement with one another (2.6 and 2.7 nM, respectively) and with values in the literature.
已对43种与可乐定结构相关的化合物进行了研究，以考察其对大鼠脑内特异性[3H]可乐定与α-肾上腺素能受体结合的抑制作用。发现氧甲唑啉是从其结合位点取代[3H]可乐定的最有效化合物。2-甲基咪唑啉、1,2,3,5-四氢咪唑并[2,1-b]喹唑啉和杂环N-甲基取代化合物对[3H]可乐定受体位点完全没有亲和力。某些2-(苯胺基)咪唑烷的降压活性与α2-肾上腺素能受体亲和力之间存在良好的相关性。对于其他化合物，也观察到了Ki值与药理活性之间的平行关系。α2-受体亲和力的明显结构要求是存在芳基部分和杂环中的N-氢。苯环上的邻位取代对于高亲和力是必要的。与相应的咪唑啉相比，具有恶唑烷环的化合物对[3H]可乐定结合位点的亲和力大致相似(2,6-二氯苯基取代的化合物除外)，而吡咯烷衍生物的亲和力则弱10倍。[3H]可乐定位点表现出均一性。饱和和置换实验得到的KD值彼此吻合良好(分别为2.6和2.7 nM)，也与文献中的值相符。
