2-Amido-8-methoxytetralins: a series of nonindolic melatonin-like agents.
A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a-q) was prepared and evaluated for their ability to compete for 2-[125I]iodomelatonin binding to chicken retinal membranes and for their potency to inhibit the calcium-dependent release of [3H]dopamine from rabbit retina. The lead compound, 2-acetamido-8-methoxytetralin (4j), showed a moderate affinity (Ki = 46 nM) and potency (IC50 = 1.4 nM) at the melatonin receptor. The structural requirements necessary for optimal agonistic activity at the melatonin receptor are as follows. First, the amido group, which should have a small, nonbranched alkyl group, is essential for affinity, and second, the methoxy substituent at the 8-position of the 2-amidotetralin ring is essential for optimal agonistic activity at the melatonin receptor. We concluded that this series of unsubstituted and methoxy-substituted 2-amidotetralins constitutes a class of nonindolic melatonin-like agents that can be used as pharmacological tools to further characterize melatonin receptors and to elucidate the mode of action of melatonin.
Copinga
S
S
Department of Medicinal Chemistry, University Centre for Pharmacy, University of Groningen, The Netherlands.
Tepper
P G
PG
Grol
C J
CJ
Horn
A S
AS
Dubocovich
M L
ML
D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002645:Chickens; D004298:Dopamine / Q000378:metabolism; D007457:Iodine Radioisotopes; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D044094:Receptors, Melatonin; D012160:Retina / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D007457:Iodine Radioisotopes; D011956:Receptors, Cell Surface; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; C083593:2-acetamido-8-methoxytetralin; D008550:Melatonin; D002118:Calcium; D004298:Dopamine