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403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene-methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats.The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment.Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.

A series of eight substrate molecules (substituted phenethylamines, guanethidine, and bretylium) had slightly less affinity for striatal than for hypothalamic synaptosomal uptake receptors as judged by ratios of striatal (s) to hypothalamic (h) IC50 values (s/h average = 3.9; range 2.0--6.0). Catecholamine uptake in striatum was very insensitive to tricyclic antidepressant inhibitors, whereas catecholamine uptake in hypothalamus was very sensitive to these agents (s/h average = 233; range 24--570). By way of contrast with both the substrates and the tricyclic inhibitors, the inhibitors with less rigidly fixed rings or analogous groups (deoxypipradrol, methylphenidate, cocaine) were potent in both brain preparations (s/h average = 1.2; range 0.6--2.3). It is concluded that the rings of nontricyclic inhibitors are able to bind to appropriate hydrophobic binding groups in both receptors, that these receptive groups have different topography in striatum and in hypothalamus, and that the topography in the striatum is incompatible with binding tricyclic systems. The data also indicate that there is great similarity, if not identity, in the receptive area for substrates in striatum and hypothalamus. Although the substrates and inhibitors bind to some groups in common in this substrate receptive area, it is the surrounding hydrophobic molecular environment that is clearly different and permits the phenomenon of selective blockade with drugs.

The pharmacology of the enantiomers of threo-methylphenidate (MPH) was evaluated in the rat to assess the relative contribution of each isomer to central and peripheral actions of the racemic drug. Fractional recrystallization of binaphthyl phosphate salts of dl-threo-MPH allowed resolution of d-threo-MPH and 92% enrichment of l-threo-MPH. The enantiomeric disposition was monitored using gas chromatographic separation of trifluoroacetylprolyl diastereomeric derivatives. The activity of the d-isomer was greater than the l-isomer in the induction of locomotor activity and the inhibition of tritiated dopamine and l-norepinephrine uptake into striatal and hypothalamic synaptosomes, respectively. Neither isomer produced a significant change in the spontaneous release of tritiated catecholamines from synaptosomes. Destruction of catecholaminergic neurons by 6-hydroxydopamine pretreatment attenuated the locomotor response to d-threo-MPH, indicating the involvement of catecholaminergic neural pathways in the locomotor response. Only the d-enantiomer significantly potentiated the pressor responses to i.v. l-norepinephrine. Receptor site stereoselectively for threo- vs. erythro-MPH is discussed in terms of isomer conformational preferences. These results suggest that synaptic inhibition of catecholamine uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.

The ATP-Mg++-dependent uptake of [3H]dopamine and l-[3H]norepinephrine into purified synaptic vesicles of whole rat brain, rat striatum and rat hypothalamus was inhibited 10-fold more effectively by S-(+)-amphetamine as compared to its corresponding (R-(-)-enantiomer. In contrast, S-(+)-deoxypipradrol and its R-(-)-enantiomer were approximately equipotent inhibitors of 3H-amine uptake into these synaptic vesicular preparations. The 1R:2R-methylphenidate was twice as potent as its 1R:2S-enantiomer as an inhibitor of 3H-catecholamine uptake. These data suggest that the receptor sites on the amine pumps present in the membranes of all three vesicular preparations are similar in so far as they are all sensitive to the stereochemical configuration around the alpha-carbon of amphetamine but are not sensitive to the stereochemical configuration around the analogous carbon of deoxypipradrol and methylphenidate. These observations are the reverse of those previously observed for the phenethylamine pumps present in peripheral and central neuronal membranes.