Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.
A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n propyl urea derivative (27) is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This molecule, compound 12, or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclinical development.
Leclerc
V
V
Institut de Chimie Pharmaceutique, Lille, France.
Fourmaintraux
E
E
Depreux
P
P
Lesieur
D
D
Morgan
P
P
Howell
H E
HE
Renard
P
P
Caignard
D H
DH
Pfeiffer
B
B
Delagrange
P
P
Guardiola-Lemaître
B
B
Andrieux
J
J
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D005260:Female; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives*; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044094:Receptors, Melatonin; D013329:Structure-Activity Relationship
D000577:Amides; C116526:N-(2-(1-naphthyl)ethyl)cyclobutylcarboxamide; D009281:Naphthalenes; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D008550:Melatonin