Design and synthesis of new N1 and C3-substituted 4-fluoroindolic melatoninergics.
A series of new C-3 and N1-substituted 4-fluorotryptamides have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. Planar sp(2) geometry at C-3-betaC seems to decrease the population of the preferred conformation as it renders 4-fluoroindoles 4b-d weaker antagonists than their C-3-betaC-unsubstituted congeners 3a-e. This effect is not preclusively linked with the C-3 region, as the same geometry around N1 (compounds 5a-c) similarly leads to weak antagonistic action. Last, the new C-3 substituted 4-fluorotryptamides presented herein are substantially more potent than their respective N-OMe functionalized congeners, previously reported.
Tsotinis
Andrew
A
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 15771 Athens, Greece. tsotinis@pharm.uoa.gr
Eleutheriades
Andreas
A
Davidson
Kathryn
K
Sugden
David
D
D000818:Animals; D002845:Chromatography / Q000379:methods; D015195:Drug Design; D006801:Humans; D007192:Indenes / Q000737:chemistry; D007211:Indoles / Q000737:chemistry*; D007457:Iodine Radioisotopes; D013058:Mass Spectrometry; D008547:Melanophores / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008550:Melatonin / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011869:Radioligand Assay; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors / Q000235:genetics; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors / Q000235:genetics; D044366:Transition Temperature; D014363:Tryptamines / Q000737:chemistry; D014982:Xenopus laevis
D007192:Indenes; D007211:Indoles; D007457:Iodine Radioisotopes; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D014363:Tryptamines; C057154:luzindole; C495910:ramelteon; D008550:Melatonin