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Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine‐resistant uptake mechanism of central and peripheral monoamine neurones in vivo and in vitro

1969; Wiley; Volume: 36; Issue: 1 Linguagem: Inglês

10.1111/j.1476-5381.1969.tb08299.x

1476-5381

Arvid Carlsson, Kjell Fuxé, Bertil Hamberger, T. Malmfors,

Pharmacological Receptor Mechanisms and Effects

Bicyclic compounds with potential thymoleptic properties (Lu‐compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs. Biochemical and histochemical in vivo studies have been performed. The possible blocking action of Lu‐compounds on the noradrenaline (NA) and 5‐hydroxytryptamine (5‐HT) displacement caused by 4,α‐dimethyl‐meta‐tyramine (H 77/77) and 4‐methyl‐α‐ethyl‐meta‐tyramine (H 75/12), respectively, has been studied, and a positive result has been taken as evidence for membrane pump blocking activity. No certain effects were obtained on the 5‐HT displacement induced by H 75/12, whereas a partial blockade of the NA displacement by H 77/77 in central NA neurones was obtained after most of the Lu‐compounds (Lu‐3–010, 3–049, 3–092, 4–012) and especially after the thiophthalane derivative Lu 5–003. The ED50 of the latter drug was around 8 mg/kg, that is, somewhere between protriptyline (ED50 4 mg/kg) and desipramine (ED50 15 mg/kg) in potency. Histochemical in vivo studies on the rat iris revealed that Lu 5–003 and especially the corresponding phthalane derivative Lu 3–010 were potent in blocking the uptake of α‐methyl‐NA in the adrenergic nerve terminals of the iris. The other Lu‐compounds were less active. The releasing effects of the Lu‐compounds on the extragranular accumulation of α‐methyl‐NA in the adrenergic terminals were weak compared with membrane blocking activity. In vitro studies on the central and peripheral catecholamine (CA) neurones have also been performed. In the same way as, for example, protriptyline the Lu‐compounds only blocked accumulation of α‐methyl‐NA in the NA terminals but not in the dopamine (DA) nerve terminals. Lu 5–003 and Lu 3–010 were the most potent of the Lu‐drugs when added in vitro . The Lu‐drugs were also injected in vivo after which the effect on the α‐methyl‐NA accumulation was studied in vitro. In isotope experiments with labelled α‐methyl‐NA it was found that desipramine, Lu‐3–010, Lu 3–092 and Lu 4–012 were equally potent in blocking uptake in the central nervous system. In general the results obtained with the various models are in agreement. The high activity of Lu 5–003 on the central NA neurones may be related to its high heptane/H 2 O distribution coefficient. It is concluded that the Lu‐compounds have a selective action on the membrane pump mechanism of the central and peripheral NA neurones. In these respects they behave like desipramine and protriptyline.