Melatonergic properties of the (+)- and (-)-enantiomers of N-(4-methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives.
N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives, conformationally restricted ligands for melatonin receptors, were synthesized by an alternative synthetic method from the corresponding 1,8-naphthalic anhydride which was transformed into the phenalenecarboxylic acid 7. A Curtius reaction on 7 gave the amino compound which was acylated to give compounds 4a-c. The (+)- and (-)-4a-c enantiomers were separated by semipreparative chiral HPLC. Compounds were evaluated for their affinity for chicken brain melatonin receptors in binding assays using 2-[125I]iodomelatonin and for their potency to lighten the skin of Xenopus laevis tadpoles. The butyramido derivative 4c was the most potent ligand (Ki = 1.7 nM). No enantioselectivity was observed with the enantiomers which were equipotent to the racemic mixture. In contrast to the reference compounds, melatonin, agomelatine (S 20098), and N-[2-(2, 7-dimethoxynaphth-1-yl)ethyl]acetamide, which were very potent at lightening the skin of X. laevis tadpoles, compounds 4a-c were inactive or weakly active (EC50 > 1 microM). In this bioassay, compound 4a was characterized as a putative antagonist of melatonin receptors.
Jellimann
C
C
CNRS-BIOCIS (URA 1843), Faculté de Pharmacie, Université de Paris-Sud, 5 rue J. B. Clément, 92296 Châtenay-Malabry, France.
Mathé-Allainmat
M
M
Andrieux
J
J
Renard
P
P
Delagrange
P
P
Langlois
M
M
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002645:Chickens; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D008024:Ligands; D008550:Melatonin / Q000031:analogs & derivatives / Q000378:metabolism*; D043803:Phenalenes; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044094:Receptors, Melatonin; D012867:Skin / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000081:Acetamides; D008024:Ligands; C118222:N-(4-methoxy-2,3-dihydro-1H-phenalen-2-yl)acetamide; D043803:Phenalenes; D011083:Polycyclic Compounds; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; C044556:2-iodomelatonin; D008550:Melatonin