Design, synthesis and in vitro evaluation of novel benzo[b]thiophene derivatives as serotonin N-acetyltransferase (AANAT) inhibitors.
Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is the penultimate enzyme in melatonin (5-methoxy-N-acetyltryptamine) biosynthesis. It is the key-enzyme responsible of the nocturnal rhythm of melatonin production in the pineal gland. Specific AANAT inhibitors could be useful for treatment of different physiopathological disorders encountered in diseases such as seasonal affective disorders or obesity. On the basis of previous works and 3D-QSAR studies carried out in our laboratory, we have synthesized and evaluated four novel benzo[b]thiophene derivatives designed as AANAT inhibitors. Compound 13 exhibited high inhibitory activity (IC50 = 1.4 microM) and low affinities for both MT, (1100 nM) and MT2 (1400 nM) receptors.
Mesangeau
C
C
Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et Biologiques, BP 83, 59006 Lille Cedex, France.
Yous
S
S
Chavatte
P
P
Ferry
G
G
Audinot
V
V
Boutin
J A
JA
Delagrange
P
P
Bennejean
C
C
Renard
P
P
Lesieur
D
D
D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D013876:Thiophenes; C088015:benzothiophene; D001191:Arylamine N-Acetyltransferase