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

Abstract

The contractions induced by a partial α1-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial α1- adrenoceptor agonist increases when the temperature is raised, a response that contrasts to that noted with full α1- and α2-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 α-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 α2-agonist (34b), a full α1-agonist (7s), and a nonselective partial α1/α2-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.