Synthesis and conformational study of 3,4-carbocyclic bridged indole melatonin and serotonin analogues.
Tetrahydrobenz[cd]indole, has been usually assumed to be a rigid scaffold of arylethylamines of pharmaceutical interest, such as melatonin and serotonin. A series of molecules containing this scaffold has been synthesized and their conformation in solution has been determined by 1H NMR. The values of the coupling constants show that the carbocycle fused with the indole ring is a mixture of the two conformers with substituent in equatorial or axial orientation. The molar fraction of the conformers appears to be sensibly affected by the bulkiness of the C-2 indole substituent. A pseudo-axial orientation of the C-3 alkylamido side chain is important for melatonin ligands to access the binding site and exhibit potent in vitro affinity, as illustrated for melatonin ligand 1 (pK(i)=9.32).
Bedini
Annalida
A
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino Carlo Bo, Piazza Rinascimento 6, I-61029 Urbino, Italy.
Di Giacomo
Barbara
B
Gatti
Giuseppe
G
Spadoni
Gilberto
G
D002255:Carbonic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D003500:Cyclization; D006859:Hydrogen / Q000737:chemistry; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008550:Melatonin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D044094:Receptors, Melatonin / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism
D007211:Indoles; D008024:Ligands; D044094:Receptors, Melatonin; D012701:Serotonin; D002255:Carbonic Acid; D006859:Hydrogen; C030374:indole; D008550:Melatonin