A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy). N-methyl-3-phenylpropylamine.
3-(p-Trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140) competitively inhibited the uptake of serotonin (5-HT), norepinephrine (NE) and dopamine into synaptosomes of rat brain with Ki values of 5.5 x 10-minus8, 9.5 x 10-minus6 and 1.3 x 10-minus5 M, respectively. Aiming for a more effective inhibitor of 5-HT uptake, we found the trifluoromethyl group in the phenoxy ring was most favorable at the para-position and was better than other substituting groups including fluoro, chloro, methyl and methoxy groups. The N-demethylated (primary amine) and the N.N-diemthylated (tertiary amine) derivatives inhibited the uptake of monoamines with the same effectiveness as Lilly 110140 (a secondary amine). The uptake of 5-HT into synaptosomes was significantly inhibited 15 minutes after an intraperitoneal administration of Lilly 110140. The inhibition persisted for a 24-hour period. NE uptake in vitro maintained a normal rate during the entire time course. Lilly 110140 likewise had no effect on the in vitro and in vivo accumulation of 3-H-tryptophan in the brain. The effect of Lilly 110140 and the tricyclic drug, chlorimipramine, was compared. Although chlorimipramine inhibited the uptake of 5-HT into synaptosomes with same effectiveness as Lilly 110140 in vitro, it reduced the uptake of both 5-HT and NE in vivo. Chlorimipramine exerted its greatest inhibition on the two uptake processes in the 1st hour and none by the 4th hour. Unlike the tricyclic drugs, imipramine, chlorimipramine, desipramine and chlordesipramine, Lilly 110140 and its primary amine derivative did not block the in vivo uptake of NE into rat heart. The present study suggests that Lilly 110140 is a potent and selective inhibitor for uptake of 5-HT into synaptosomes of rat brain.
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001921:Brain / Q000648:ultrastructure*; D003864:Depression, Chemical; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010647:Phenyl Ethers / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D010647:Phenyl Ethers; D011437:Propylamines; D012701:Serotonin; D014364:Tryptophan; D004298:Dopamine; D009638:Norepinephrine