Studies on the peripheral pharmacology of fenazoxine, a potential antidepressant drug.

1. The action of fenazoxine, a cyclized analogue of orphenadrine, has been studied on peripheral tissues innervated by adrenergic and cholinergic nerves. The hypothesis that cyclization of the alkyl amino chain of orphenadrine results in a molecule which retains the noradrenaline sensitizing action of orphenadrine but lacks the antimuscarinic activity has been investigated.2. The antimuscarinic activity of fenazoxine, on guinea pig ileum, was approximately 1/30 that of orphenadrine.3. Fenazoxine, desmethylimipramine and cocaine potentiated the response to noradrenaline and sympathetic nerve stimulation on the cat nictitating membrane, isolated rabbit ear artery and isolated driven atrial strip preparations.4. On the driven atrial strip preparation, fenazoxine at concentrations of 5 x 10(-7)M and 1 x 10(-6)M produced a small potentiation of the inotropic response to isoprenaline. At 5 x 10(-6)M and 5 x 10(-5)M fenazoxine antagonized the inotropic response to tyramine.5. Chronic denervation of the cat nictitating membrane abolished the potentiating action of fenazoxine.6. The results presented suggest that fenazoxine inhibits the uptake of catecholamines in a manner similar to that reported for desmethylimipramine and cocaine.7. Evidence is also presented which suggests that fenazoxine, like desmethylimipramine, possesses anti-noradrenaline activity at higher concentrations.