Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: synthesis, binding affinity and intrinsic activity for MT(1) and MT(2) melatonin receptors.

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Spadoni G, Bedini A, Orlando P, Lucarini S, Tarzia G, Mor M, Rivara S, Lucini V, Pannacci M, Scaglione F

Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: synthesis, binding affinity and intrinsic activity for MT(1) and MT(2) melatonin receptors.

Bioorg Med Chem. 2011 Aug 15;19(16):4910-6. doi: 10.1016/j.bmc.2011.06.063. Epub 2011 Jun 28.

PubMed ID

21775151 [ View in PubMed

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Abstract

We report the synthesis, binding properties and intrinsic activity at MT(1) and MT(2) 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 MT(1) receptor, and to a partial agonist behavior. Compound 3a, with a trimethylene linker, was the most selective for the MT(1) subtype (112-fold selectivity) and compound 3d, characterized by a hexamethylene spacer, had the highest MT(1) binding affinity (pK(iMT1)=8.47) and 54-fold MT(1)-selectivity. Dimerization through the aniline nitrogen of 1 abolished MT(1) selectivity, leading to compounds with either a full agonist or an antagonist behavior depending on the nature of the linker.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Melatonin	Melatonin receptor type 1A	Ki (nM)	0.263	N/A	N/A	Details
Melatonin	Melatonin receptor type 1B	Ki (nM)	0.339	N/A	N/A	Details