Alaproclate, a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia

Abstract

Alaproclate, a new specific 5-HT uptake inhibitor, was examined for its action on several receptors in the brain, for its action on the NA, DA and 5-HT uptake mechanisms in vivo and for its action on brain biogenic amine content. Alaproclate was practically devoid of action on a number of receptors as examined in binding studies in vitro: 5-HT, histamine-H1, alpha 1, -alpha 2-adrenergic and dopamine D2 receptors. Alaproclate had also a weak affinity for 3H-norzimeldine binding sites in contrast to imipramine. Unlike the tricyclic antidepressants alaproclate had a negligible action on muscarinic receptors and failed to block muscarinic induced stimulation in vivo. Contrary to clomipramine alaproclate failed to block NA uptake in vivo. Alaproclate was found to display a regional selectivity in blocking 5-HT uptake in vivo (measured with the H 75/12-method). The compound was most potent in the hippocampus and hypothalamus followed by striatum and cerebral cortex with a low potency in the spinal cord. The results are discussed in relation to a previously presented carrier site model for serotonin reuptake.

The effect of selective 5‐hydroxytryptamine uptake inhibitors on 5‐methoxy‐N,N‐dimethyltryptamine‐induced ejaculation in the rat

“…Ogren et al, 1984). The development ofthe long-lasting decrease of the ejaculatory response after a single dose of fluoxetine or zimeldine may also be explained by an influence of these drugs on the postsynaptic receptors involved in the ejaculatory response.…”

Synthesis and 3H NMR of 3H‐alaproclate of high specific activity

“…The residue was flash chromatographed on 1-(2,5-Di bromo-4-chlorophenyl)-2-methyl-2-propanol (2). TLC and GLC showed complete conversion a f t e r…”

“…' The agent i s a selective i n h i b i t o r of the neuronal serotonin reuDtake.2 I t s low a f f i n i t y f o r other receptor s i t e s prompted the synthesis o f 3H-labe11ed alaproclate f o r binding studies. 2 Material with an a c t i v i t y of more than 35 C i / m l was required, i.e. a mininun o f two t r i t i u n a t o m per molecule.…”

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

“…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.…”