Pharmacological and biochemical studies on a new compound, 2-(7-indeyloxymethyl)morpholine hydrochloride (YM-08054-1), and its derivatives with potential antidepressant properties.
Antidepressant properties of a new indene derivative, YM-08054-1, and its related compounds were compared with those of tricyclic antidepressants and viloxazine. The potencies of YM-08054-1 to inhibit uptake of both 14C-norepinephrine (14C-NE) and 14C-5-hydroxytryptamine (14C-5-HT) by the rat brain synaptosomes were similar to those of amitriptyline and imipramine. Other indene derivatives with an N-alkylated morpholine ring were proved to have less effect on the uptake of either 5-HT or NE than was YM-08054-1. YM-08054-1 was the most potent among all of the tested antidepressants in the inhibition of reserpine-induced facilitation of convulsions as well as in the potentiation of reserpine-induced facilitation of convulsions as well as in the potentiation of 5-hydroxytryptophan (5-HTP)-induced syndromes in mice, though the inhibitory effect of this agent on reserpine-induced hypothermia was weaker than that of either amitriptyline or desipramine, suggesting relatively selective effects of YM-08054-1 upon 5-HT rather than NE uptake in vivo. Neither viloxazine nor iprindole potentiated the responses to 5-HTP. YM-08054-1 was devoid of peripheral anticholinergic activity and exhibited weak local anesthetic effect as well as low acute toxicity when compared with amitriptyline. The results indicate that YM-08054-1 has a novel profile as an antidepressant agent which is quite different from that of either viloxazine or tricyclic compounds.
D000779:Anesthetics, Local; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007192:Indenes / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology* / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism; D010276:Parasympatholytics; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D012110:Reserpine / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D000779:Anesthetics, Local; D000928:Antidepressive Agents; D007192:Indenes; D009025:Morpholines; D010276:Parasympatholytics; D010627:Phenethylamines; D012701:Serotonin; C020852:indeloxazine; D012110:Reserpine; D009638:Norepinephrine