Studies on the biochemical mode of action of EGYT-475, a new antidepressant.
We studied the mode of action of N-benzyl-piperazine-picolinylfumarate (EGYT-475) and of its metabolite N-benzyl-piperazine (EGYT-2760) in CFY rats. It was found that EGYT-475 had no uptake-inhibitory effect but EGYT-2760 inhibited the high-affinity uptake of 3H-noradrenaline, 3H-dopamine and especially that of 3H-serotonin both in vitro and ex vivo. Neither of the two compounds changed the serotonin turnover. Only EGYT-2760 evoked hyperthermia in rats at a high ambient temperature (28 degrees C). This effect was abolished by cyproheptadine but not by amitriptyline. EGYT-2760 antagonized serotonin-induced contractions of the stomach fundus but it was inactive in inhibiting the serotonin-induced platelet aggregation. Our results suggest that EGYT-2760, an active metabolite of EGYT-475, has a central serotoninomimetic action which involves 5-HT uptake-inhibition and 5-HT1 receptor agonistic effect.
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D015237:Dinoprost; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D010879:Piperazines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011460:Prostaglandins F / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013270:Stomach / Q000187:drug effects
D000928:Antidepressive Agents; D010879:Piperazines; D011460:Prostaglandins F; D012701:Serotonin; C040401:EGYT 475; C006737:1-benzylpiperazine; D006897:Hydroxyindoleacetic Acid; D015237:Dinoprost