Neuropharmacology 1985-12-01

Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug.

C Moret, M Charveron, J P Finberg, J P Couzinier, M Briley

文献索引：Neuropharmacology 24 , 1211-1219, (1985)

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摘要

The present study of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane(Z) hydrochloride, was undertaken to determine its biochemical profile. The properties of midalcipran, in inhibiting the uptake of monoamines were tested and compared with that of imipramine. In vitro, midalcipran was found to inhibit the uptake of radiolabelled serotonin and noradrenaline (IC50 = 203 and 100 nM, respectively), but not that of dopamine, into brain slices. Hyperthermia induced by the centrally-acting displacers of monoamines, H77/77 and H75/12, were almost equipotently antagonized by midalcipran, confirming the inhibition of the uptake of serotonin and noradrenaline by midalcipran in vivo (ID50 = 11 and 4.8 mg/kg, respectively). Midalcipran showed no inhibition of the activity of monoamine oxidase in vitro or in vivo. The interaction between midalcipran and neurotransmitter receptors and binding sites in the CNS was studied in the rat in comparison with imipramine and desipramine. In contrast to these two antidepressant drugs, midalcipran showed no affinity for alpha- or beta-adrenoceptors, muscarinic, histaminergic H1, dopaminergic D2 or serotonergic 5-HT2 receptors, suggesting a general absence of anticholinergic, sedative and other side-effects. Midalcipran was equipotent with imipramine at inhibiting the binding of [3H]imipramine. Chronic administration of midalcipran to rats did not alter the number of beta-adrenergic receptors in the cortex, in contrast to imipramine and desipramine which decreased the binding of beta-adrenoceptors. Thus midalcipran appears to act exclusively presynaptically, inhibiting the uptake of serotonin and noradrenaline. This activity, coupled to the total absence of interaction at postsynaptic sites, suggests that midalcipran may be a useful and novel antidepressant drug.