CHEMICAL STRUCTURE AND ANTISHOCK ACTIVITY AMONG COMPOUNDS RELATED TO PHENOXYBENZAMINE (DIBENZYLINE)

¹ Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, Winnipeg, Canada

Phenoxybenzamine and four congeners were investigated in an attempt to correlate ability to protect against hemorrhagic shock in dogs with pharmacological activity and chemical structure. Particular attention was paid to the roles of adrenergic blocking activity (present in phenoxybenzamine, minimal in SKF-5331 and absent in GD-131, GD-12 and SKF-1010) and of a reactive -haloalkylamine grouping (present in phenoxybenzamine and GD-131 and absent in the other agents tested).

Phenoxybenzamine, in a dose providing a considerable degree of adrenergic blockade during the period of hemorrhagic stress, markedly reduced mortality without significantly reducing bleeding volumes. Pretreatment with GD-131 appeared to decrease the mortality rate somewhat. However, this was accompanied by a significant decrease in bleeding volumes and therefore, cannot be considered an expression of a specific antishock effect. This agent increased both the blood pressure and hematocrit, effects which suggest that increased sympathetic nervous system activity may have contributed to both the mortality and the decreased bleeding volumes. SKF-5331, GD-l2 and SKF-1010 provided no protection in the doses employed.

The present results indicate that the antishock properties of phenoxybenzamine are related to its adrenergic blocking activity. Both the reactive -halogen and an appropriate aromatic group (phenoxyisopropyl, benzyl, etc.) are necessary structural components for this activity. A reactive -halogen or a phenoxyisopropyl and/or benzyl grouping alone is inadequate to protect against hemorrhagic shock.