Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties.
The pharmacological profile of a new bicyclic substance, Lu 10-171 (1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitril), is described and compared with that of existing tricyclic thymoleptics. In mice and rats the compound exhibited marked 5-HT potentiating properties both in vivo and in vitro, being 5-10 times as active as chlorimipramine. The tests included 5-HT-, 5-HTP- and tryptophan-potentiation. In monoamine oxidase inhibitor treated dogs and rabbits the compound caused a marked hyperthermia. In rabbits this effect was completely blocked by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Hyperthermia induced by the central catecholamine displacing substance H 77/77 in rats was not affected by Lu 10-171, whereas the substance abolished the temperature rise induced by H 75/12. Reserpine- and tetrabenazine-induced ptosis and tetrabenazine-induced immobility in mice were antagonized by relatively low doses of existing tricyclic thymoleptics, whereas Lu 10-171 was very weak in this respect. Very weak in vitro anticholinergic and antihistaminergic properties were also registered for Lu 10-171. It is concluded that Lu 10-171 is a very potent and highly specific potentiator of 5-HT both in vivo and in vitro probably due to inhibition of 5-HT uptake. Thus this compound might be a useful agent in studying the role of 5-HT neurone systems in the control of mood. The substance does not possess the NA potentiating and anticholinergic and antihistaminergic properties characteristic of the tricyclic antidepressants.
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D003864:Depression, Chemical; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006634:Histamine H1 Antagonists; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010276:Parasympatholytics; D011817:Rabbits; D051381:Rats; D012110:Reserpine / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D013045:Species Specificity; D013747:Tetrabenazine / Q000037:antagonists & inhibitors; D014364:Tryptophan / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D001572:Benzofurans; D006634:Histamine H1 Antagonists; D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D010276:Parasympatholytics; D012701:Serotonin; D012110:Reserpine; D014364:Tryptophan; D006916:5-Hydroxytryptophan; D013747:Tetrabenazine