Synthesis and Structure-Activity Relationships of Novel Naphthalenic and Bioisosteric Related Amidic Derivatives as Melatonin Receptor Ligands

A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relation...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-09, Vol.37 (20), p.3231-3239
Main Authors: Depreux, Patrick, Lesieur, Daniel, Mansour, Hamid Ait, Morgan, Peter, Howell, H. Edward, Renard, Pierre, Caignard, Daniel-Henri, Pfeiffer, Bruno, Delagrange, Philippe
Format: Article
Language:English
Subjects:
Acetamides - chemical synthesis
Acetamides - metabolism
Acetamides - pharmacology
Animals
Biological and medical sciences
Cell Membrane - metabolism
Colforsin - pharmacology
Cyclic AMP - biosynthesis
General pharmacology
Iodine Radioisotopes
Ligands
Medical sciences
Melatonin - metabolism
Melatonin - pharmacology
Molecular Structure
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Pituitary Gland, Anterior - metabolism
Receptors, Cell Surface - metabolism
Receptors, Melatonin
Sheep
Structure-Activity Relationship
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Summary:A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analogue was a poor ligand. Compound 7, the naphthalenic analogue of melatonin, a selective ligand of the melatonin receptor and an agonist derivative, has been selected for clinical development.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00046a006