Design, synthesis, and structure-activity relationships of a new series of alpha-adrenergic agonists: spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)].

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.