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

Abstract

. 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. . The antimuscarinic activity of fenazoxine, on guinea pig ileum, was approximately 1/30 that of orphenadrine. . 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. . On the driven atrial strip preparation, fenazoxine at concentrations of 5 × 10−7M and 1 × 10−6M produced a small potentiation of the inotropic response to isoprenaline. At 5 × 10−6M and 5 × 10−5M fenazoxine antagonized the inotropic response to tyramine. . Chronic denervation of the cat nictitating membrane abolished the potentiating action of fenazoxine. . The results presented suggest that fenazoxine inhibits the uptake of catecholamines in a manner similar to that reported for desmethylimipramine and cocaine. . Evidence is also presented which suggests that fenazoxine, like desmethylimipramine, possesses anti‐noradrenaline activity at higher concentrations.

Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception

“…Relevant to the present results are previous findings of a synergistic interaction between orphenadrine (a muscle relaxant with antinociceptive effects) and paracetamol in human and animal studies, 49,50 because nefopam is considered a cyclic analogue of orphenadrine. 51 Although measurements of behaviour and motor activity were not specified in the study protocols, the combination of the two drugs did not induce impairments in gross behaviour of animals or in motor activity (in any protocol or at any of the doses tested).…”

Adrenergic Mechanisms in the Rabbit Ear Artery

“…This is despite widely different effects on intraluminal NE sensitivity, ranging from poten tiation by guanethidine, which is considerably greater than that produced by cocaine or chronic denervation [37], to depression by protryptyline [43]. Although desipramine and fenazoxine, like protryptyline, possess both cocaine-like and depressant actions on this artery, their effects on intraluminal NE sensitivity do not appear to have been reported [34,44].…”

Effects of McN‐A‐343 and DMPP on the uptake and release of 3H‐noradrenaline by guinea‐pig atria

“…These effects are indubitably a consequence of inhibition of neuronal uptake of these amines. There was a slight potentiation of responses to isoprenaline, as occurs with other inhibitors of neuronal uptake (Basset, Cairncross, Hacket & Story, 1969). Inhibition of uptake by McN-A-343 must be taken into account when evaluating its interaction with adrenergic mechanisms.…”

“…These effects are indubitably a consequence of inhibition of neuronal uptake of these amines. There was a slight potentiation of responses to isoprenaline, as occurs with other inhibitors of neuronal uptake (Basset, Cairncross, Hacket & Story, 1969 (Rand & Varma, 1971). Furthermore, other cholinomimetic drugs, including acetylcholine, methacholine and pilocarpine, also facilitated responses of the ear artery to sympathetic nerve stimulation under certain circumstances (Rand & Varma, 1970); however these cholinomimetics were considerably less active than McN-A-343 in inhibiting noradrenaline uptake (Allen, Rand & Story, unpublished observations).…”