Cordi A A, Lacoste J M, Descombes J J, Courchay C, Vanhoutte P M, Laubie M, Verbeuren T J
Institut de Recherches Servier, Suresnes, France.
J Med Chem. 1995 Sep 29;38(20):4056-69. doi: 10.1021/jm00020a021.
The contractions induced by a partial alpha 1-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial alpha 1-adrenoceptor agonist increases when the temperature is raised, a response that contrasts to that noted with full alpha 1- and alpha 2-adrenoceptor agonists. This observation may be of importance for the treatment of the symptoms of venous insuffiency, favored during warm summer days. A new series of full and partial alpha-adrenergic agonists was designed and synthesized, the spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)] 7a-kk or spiro-imidazolines. Using in vitro (femoral artery and saphenous vein) and in vivo (pithed rat) biological evaluations, structure-activity relationships could be defined which allowed the discovery of a full alpha 2-agonist (34b), a full alpha 1-agonist (7s), and a nonselective partial alpha 1/alpha 2-agonist (7aa) endowed with an outstanding veinotonic selectivity as compared to its effect on mean arterial pressure. The latter compound is presently undergoing extensive pharmacological and toxicological evaluations, as a clinical candidate.
局部α1 -肾上腺素能受体激动剂在诸如隐静脉等皮肤静脉中诱导的收缩对局部温度变化表现出特殊的敏感性：当温度升高时，对局部α1 -肾上腺素能受体激动剂的收缩性增加，这一反应与完全α1 -和α2 -肾上腺素能受体激动剂所观察到的情况形成对比。这一观察结果对于治疗在温暖夏日里更易出现的静脉功能不全症状可能具有重要意义。设计并合成了一系列新的完全和部分α -肾上腺素能激动剂，即螺[(1,3 -二氮杂环戊 - 1 -烯)-5,2'-(1',2',3',4'-四氢萘)] 7a - kk或螺 -咪唑啉。通过体外（股动脉和隐静脉）和体内（去大脑大鼠）生物学评估，可以确定构效关系，从而发现一种完全α2 -激动剂（34b）、一种完全α1 -激动剂（7s）以及一种非选择性部分α1/α2 -激动剂（7aa），与对平均动脉压的影响相比，该非选择性部分α1/α2 -激动剂具有出色的静脉张力选择性。后一种化合物目前正在作为临床候选药物进行广泛的药理学和毒理学评估。
