Synthesis and structure-affinity-activity relationships of novel benzofuran derivatives as MT(2) melatonin receptor selective ligands.
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Wallez V, Durieux-Poissonnier S, Chavatte P, Boutin JA, Audinot V, Nicolas JP, Bennejean C, Delagrange P, Renard P, Lesieur D
Synthesis and structure-affinity-activity relationships of novel benzofuran derivatives as MT(2) melatonin receptor selective ligands.
J Med Chem. 2002 Jun 20;45(13):2788-800.
- PubMed ID
- 12061881 [ View in PubMed]
- Abstract
A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT(1) and MT(2) melatonin receptor subtypes was determined by binding studies using 2-[(125)I]iodomelatonin on human embryonic kidney cell line HEK293 membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated on the [(35)S]GTPgammaS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran position leads to an agonist compound, 10q, which binds more strongly than melatonin itself to both MT(1) and MT(2) subtypes. On the other hand, a 2-benzyl group in the same position allows MT(2) antagonist selective ligands to be obtained. The MT(2) selectivity and antagonist potency can be modulated with suitable modifications on the N-acyl and benzyl substituents, and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the MT(2) subtype similarly to melatonin itself (0.1 nM). Nevertheless, 10c acts as an MT(1) and MT(2) antagonist, whereas 19 is a partial agonist.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Melatonin Melatonin receptor type 1A Ki (nM) 0.12 N/A N/A Details Melatonin Melatonin receptor type 1A EC 50 (nM) 1.92 N/A N/A Details Melatonin Melatonin receptor type 1B Ki (nM) 0.31 N/A N/A Details Melatonin Melatonin receptor type 1B EC 50 (nM) 0.47 N/A N/A Details