title: Conformationally restrained melatonin analogues: synthesis, binding affinity for the melatonin receptor, evaluation of the biological activity, and molecular modeling study.
abstract: The design, synthesis, and biological profile of several indole melatonin analogues with a conformationally restricted C3 amidoethane side chain are presented. Examination of the accessible conformations of the melatonin side chain led us to explore some of its fully or partially restricted analogues, 2-12, the binding affinity values of which were utilized to gain further insight on the melatonin binding site. Two pharmacophoric models have been devised for melatonin and the active compounds by conformational analysis and superimposition performed using the DISCO program. In these models, the melatonin side chain can adopt a gauche/anti conformation out of the indole plane. Another contribution of this study regards the observation of a possible binding point interaction around the C2 position of the indole, as suggested by the remarkably increased binding affinity observed in the C2-substituted analogues 6 and 9 and especially in the more rigid analogue 5. The biological activity and the efficacy of the new compounds were tested by measuring the inhibition of the forskolin-stimulated cAMP accumulation and the GTP gamma S index. Both analyses demonstrated that all of the compounds were full agonists with the exception of 4 and 9, which showed a slight reduction in efficacy and would seem to be partial agonists.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino, Italy. chimfarm@chim.uniurb.it
authors.forename: G
authors.initials: G
authors.lastname: Spadoni
authors.forename: C
authors.initials: C
authors.lastname: Balsamini
authors.forename: G
authors.initials: G
authors.lastname: Diamantini
authors.forename: B
authors.initials: B
authors.lastname: Di Giacomo
authors.forename: G
authors.initials: G
authors.lastname: Tarzia
authors.forename: M
authors.initials: M
authors.lastname: Mor
authors.forename: P V
authors.initials: PV
authors.lastname: Plazzi
authors.forename: S
authors.initials: S
authors.lastname: Rivara
authors.forename: V
authors.initials: V
authors.lastname: Lucini
authors.forename: R
authors.initials: R
authors.lastname: Nonno
authors.forename: M
authors.initials: M
authors.lastname: Pannacci
authors.forename: F
authors.initials: F
authors.lastname: Fraschini
authors.forename: B M
authors.initials: BM
authors.lastname: Stankov
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002645:Chickens; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D011784:Quail; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D044094:Receptors, Melatonin; D013477:Superior Colliculi / Q000187:drug effects / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D008550:Melatonin