Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT(1) melatoninergic ligands.
Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT(1)-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.
Mésangeau
Christophe
C
Univ Lille Nord de France, F-59000 Lille, France.
Pérès
Basile
B
Descamps-François
Carole
C
Chavatte
Philippe
P
Audinot
Valérie
V
Coumailleau
Sophie
S
Boutin
Jean A
JA
Delagrange
Philippe
P
Bennejean
Caroline
C
Renard
Pierre
P
Caignard
Daniel H
DH
Berthelot
Pascal
P
Yous
Saïd
S
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008550:Melatonin / Q000819:agonists; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors*; D009281:Naphthalenes
D000081:Acetamides; D008550:Melatonin; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin; C084711:agomelatine; D009281:Naphthalenes