We report the synthesis, binding properties and intrinsic activity at MT1 and MT2 melatonin receptors of new dimeric melatonin receptor ligands in which two units of the monomeric agonist N-{2-[(3-methoxyphenyl) methylamino]ethyl}acetamide (1) are linked together through different anchor points. Dimerization of compound 1 through the methoxy substituent leads to a substantial improvement in selectivity for the MT1 receptor, and to a partial agonist behavior. Compound 3a, with a trimethylene linker, was the most selective for the MT1 subtype (112-fold selectivity) and compound 3d, characterized by a hexamethylene spacer, had the highest MT1 binding affinity (pKiMT1 = 8.47) and 54-fold MT1-selectivity. Dimerization through the aniline nitrogen of 1 abolished MT1 selectivity, leading to compounds with either a full agonist or an antagonist behavior depending on the nature of the linker.

Bivalent ligand approach on N-{2-[(3 -methoxyphenyl)methylamino]ethyl}acetamide: Synthesis, binding affinity and intrinsic activity for MT1 and MT2 melatonin receptors / G., Spadoni; A., Bedini; P., Orlando; S., Lucarini; G., Tarzia; Mor, Marco; Rivara, Silvia; V., Lucini; M., Pannacci; F., Scaglione. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 19:16(2011), pp. 4910-4916. [10.1016/j.bmc.2011.06.063]

Bivalent ligand approach on N-{2-[(3 -methoxyphenyl)methylamino]ethyl}acetamide: Synthesis, binding affinity and intrinsic activity for MT1 and MT2 melatonin receptors.

MOR, Marco;RIVARA, Silvia;
2011-01-01

Abstract

We report the synthesis, binding properties and intrinsic activity at MT1 and MT2 melatonin receptors of new dimeric melatonin receptor ligands in which two units of the monomeric agonist N-{2-[(3-methoxyphenyl) methylamino]ethyl}acetamide (1) are linked together through different anchor points. Dimerization of compound 1 through the methoxy substituent leads to a substantial improvement in selectivity for the MT1 receptor, and to a partial agonist behavior. Compound 3a, with a trimethylene linker, was the most selective for the MT1 subtype (112-fold selectivity) and compound 3d, characterized by a hexamethylene spacer, had the highest MT1 binding affinity (pKiMT1 = 8.47) and 54-fold MT1-selectivity. Dimerization through the aniline nitrogen of 1 abolished MT1 selectivity, leading to compounds with either a full agonist or an antagonist behavior depending on the nature of the linker.
2011
Bivalent ligand approach on N-{2-[(3 -methoxyphenyl)methylamino]ethyl}acetamide: Synthesis, binding affinity and intrinsic activity for MT1 and MT2 melatonin receptors / G., Spadoni; A., Bedini; P., Orlando; S., Lucarini; G., Tarzia; Mor, Marco; Rivara, Silvia; V., Lucini; M., Pannacci; F., Scaglione. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 19:16(2011), pp. 4910-4916. [10.1016/j.bmc.2011.06.063]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2374097
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