New indole derivatives as potent and selective serotonin uptake inhibitors.
A series of new indole derivatives (2-28) has been prepared in the search for novel 5-HT uptake inhibitors. These compounds were obtained by the condensation of N-(chloroalkyl) naphthalenesultam derivatives with the appropriate amine in presence of a base, at reflux of DMF or THF. The yields were moderate (12-56%), except for the piperazine derivative 20 (85%). The affinity of the compounds for uptake site and 5-HT2, alpha 1, and D2 receptors was measured. Some compounds were studied in vivo by their potentiating effect of 5-HTP-induced symptomatology. The most potent and selective (uptake, 5-HT2 versus alpha 1, D2 sites) compounds contain a 3-[(4-piperidinyl)methyl]indole moiety. 5-Fluoro-3-[(4-piperidinyl)methyl]indole itself (compound 1) displayed a high affinity for the uptake site but was devoided of in vivo activity. N-Methylation of this compound abolished the affinity. In contrast N-substitution by a two-carbon chain linked to a naphthalenesultam or related heterocycle led to compounds exhibiting high affinity for the uptake site. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)methyl-1- piperidinyl]ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2- ij]quinoline 2,2-dioxide (compound 24), was found as active as fluoxetine in vivo.
Malleron
J L
JL
Départements de Chimie Pharmaceutique et de Biologie, Centre de Recherches de Vitry-Alfortville, Vitry-sur-Seine, France.
Guérémy
C
C
Mignani
S
S
Peyronel
J F
JF
Truchon
A
A
Blanchard
J C
JC
Doble
A
A
Laduron
P
P
Piot
O
O
Zundel
J L
JL
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D004298:Dopamine; D005473:Fluoxetine; D007211:Indoles; D009638:Norepinephrine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013830:Thiadiazoles; C081109:1-(2-(4-((5-fluoro-1H-indol-3-yl)methyl)-1-piperidinyl)ethyl)-5,6-dihydro-1H,4H-1,2,5-thiadiazolo(4,3,2-ij)quinoline 2,2-dioxide