Synthesis of nitroindole derivatives with high affinity and selectivity for melatoninergic binding sites MT(3).
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.
Leclerc
Véronique
V
Institut de Chimie Pharmaceutique Albert Lespagnol, 3 rue du Professeur Laguesse, BP83, 59006 Lille Cedex, France.
Yous
Saïd
S
Delagrange
Philippe
P
Boutin
Jean A
JA
Renard
Pierre
P
Lesieur
Daniel
D
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
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