title: Synthesis and conformational study of 3,4-carbocyclic bridged indole melatonin and serotonin analogues.
abstract: 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).
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino Carlo Bo, Piazza Rinascimento 6, I-61029 Urbino, Italy.
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Giacomo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gatti
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
mesh_terms: 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
chemical_list: D007211:Indoles; D008024:Ligands; D044094:Receptors, Melatonin; D012701:Serotonin; D002255:Carbonic Acid; D006859:Hydrogen; C030374:indole; D008550:Melatonin