The pharmacology of zimelidine: A 5‐HT selective reuptake inhibitor

Abstract

Zimelidine (ZIM) and its main active metabolite norzimelidine (NZIM) have been shown to preferentially inhibit 5‐hydroxytryptamine (5‐HT) neuronal uptake both in vitro and in vivo while having much less effect on noradrenaline (NA) uptake. ZIM in vivo blocked the 5‐HT uptake mechanism in the cerebral cortex, hippocampus, striatum, hypothalamus and spinal cord, thus indicating effects on both the ascending and descending 5‐HT pathways. ZIM is devoid of a 5‐HT releasing action, MAO‐inhibitory properties and effects on dopamine (DA) uptake. ZIM failed to reduce NA turnover even in high doses, but markedly reduced 5‐HT turnover in very low doses in the rat. ZIM also enhanced 5‐HT mediated behaviours in mice in doses related to the inhibition of 5‐HT uptake. In contrast to amitriptyline (AMI) and mianserin (MIAN), ZIM only in extremely high doses displayed a 5‐HT receptor blocking action in vitro and failed to block 5‐HT mediated behaviour. ZIM was practically devoid of action on histamine H1 and H2 receptors, and had also a neglible action on noradrenergic α1‐ and α2‐receptors, and on β‐receptors. Unlike the tricyclic antidepressants (TAD's) ZIM had a negligible action on muscarinic receptors and failed to affect cholinergic induced activity. Long‐term treatment with ZIM did not result in any attenuation of the 5‐HT uptake blocking potency or the reduction of 5‐HT turnover. This long‐term treatment slightly reduced the number of β‐receptors in the brain. However, repeated ZIM‐treatment induced a new 5‐HT receptor binding site characterized by a low affinity and with a high number of binding sites and decreased the number of high affinity 5‐HT receptor binding sites. Unlike the TAD's zimelidine failed to block the action of reserpine. Metabolic and behavioural interaction studies in mice showed that ZIM was devoid of any significant interactions with ethanol, barbiturates and benzodiazepines. It is concluded that ZIM markedly differs front both the TAD's and new antidepressants such as mianserin and nomifensine. ZIM seems preferentially to effect the presynaptic 5‐HT reuptake mechanism while having a negligible action on noradrenergic, 5‐HT, acetylcholine and histamine receptors in the brain.

Serotoninergic Reuptake Mechanisms in the Control of Cataplexy

“…These results indicate that zimelidine is a potent anticataplectic agent without noticeable effect on EDS. Zimelidine and its main metabolite norzimelidine are potent and selective 5-HT reuptake inhibitors both in vitro and in vivo (8,15). In our study, this action was shown by an 80% reduction of 5-HT bloodconcentration 24 h after an oral administration of 100 mg. On the other hand, zimelidine has no effect on peripheral or central cholinergic systems.…”

Similar effect on REM sleep but differential effect on slow wave sleep of the two 5-HT uptake inhibitors zimeldine and alaproclate in cats and rats

“…If anything, alaproclate is a more specific and pure reuptake inhibitor than zimeldine (Ross and Renyi, 1977;Hall and Ogren, 1981;Ogren et aL, 1984). An effect via NA uptake by norzimeldine (Ross and Renyi, 1977;Ogren et aL, 1981) would not explain the different SWS-2 effects. Increased synaptic NA would tend to increase waking (Jacobs and Jones, 1978) and reduce rather than increase SWS-2.…”

“…Unlike zimeldine (Ogren and Holm, 1980;Ogren et al, 1981), alaproclate shows regional differences in its 5-HT uptake inhibition, it has higher potency in the hippocampus and hypothalamus than in the cortex cerebrum and striatum, and low potency in the spinal cord (Ogren et al, 1984). Thus, different effects on sleep might be expected from alaproclate than from other 5-HT uptake inhibitors.…”

“…In the present study we have investigated sleep effects in cats and rats of two such new drugs, zimeldine (Ross et al, 1976;Ogren et al, 1981) and alaproclate (Lindberg et al, 1978;Ogren et al, 1984). Both drugs are selective serotonin uptake inhibitors.…”

Depression in Patients With Epilepsy

“…It is conceivable that these less favourable results are based on the relatively slight NA-potentiating effect of amitriptyline, while the favourable effect in normal or high MHPG excretors is based on its relatively marked influence on 5HT ( van Praag 1977) • Early reports suggested that clomipramine may owe its clinical efficacy to its ability to inhibit 5HT uptake (Carlsson et al 1969a;Waldmeier 1976). More recently, zimelidine, a selective 5HT re-uptake inhibitor (Ogren et al 1981) has been 0 shown to be antidepressant (Montgomery et al 1981;d'Elia et al 1981;Aberg 1981;w:linder et al 1981).…”