title: Synthesis of nitroindole derivatives with high affinity and selectivity for melatoninergic binding sites MT(3).
abstract: The aim of this study was to synthesize selective ligands for melatoninergic subtype receptors that could elucidate the physiological role of melatonin (N-acetyl-5-methoxytryptamine, 1). So, we first investigated the role of a nitro substituent in the 4-, 6-, or 7-position of the indole heterocycle. Comparatively to melatonin, its analogues that nitrated in the 6- or 7-position (6 and 22) lose MT(3) but retain good MT(1) and MT(2) affinities, whereas the 4-nitro isomer (5) shows very high affinity (nanomolar) and selectivity for the MT(3) binding sites. N-Methylation of the indole nucleus of compound 5 potentiates these effects and affords the most potent and selective MT(3) ligand (17). The 2-iodo derivatives (12 and 10) of compounds 5 and 17 have also been synthesized to evaluate their binding profile with a view to further develop MT(3) selective radioligands.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, 3 rue du Professeur Laguesse, BP83, 59006 Lille Cedex, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Leclerc
authors.forename: Saïd
authors.initials: S
authors.lastname: Yous
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Daniel
authors.initials: D
authors.lastname: Lesieur
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D044094:Receptors, Melatonin; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D007211:Indoles; D008024:Ligands; C453984:N-(2-(5-methoxy-1-methyl-4-nitroindol-3-yl)ethyl)-acetamide; D009574:Nitro Compounds; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin