7-Alkyl-3-benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists.
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Rempel V, Volz N, Hinz S, Karcz T, Meliciani I, Nieger M, Wenzel W, Brase S, Muller CE
7-Alkyl-3-benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists.
J Med Chem. 2012 Sep 27;55(18):7967-77. Epub 2012 Sep 11.
- PubMed ID
- 22916707 [ View in PubMed]
- Abstract
A series of 7-alkyl-3-benzylcoumarins was designed, synthesized, and tested at cannabinoid CB(1) and CB(2) receptors in radioligand binding and cAMP accumulation studies. 7-Alkyl-3-benzylcoumarins were found to constitute a versatile scaffold for obtaining potent CB receptor ligands with high potency at either CB(1) or CB(2) and a broad spectrum of efficacies. Fine-tuning of compound properties was achieved by small modifications of the substitution pattern. The most potent compounds of the present series include 5-methoxy-3-(2-methylbenzyl)-7-pentyl-2H-chromen-2-one (19a, PSB-SB-1201), a selective CB(1)antagonist (K(i) CB(1) 0.022 muM), 5-methoxy-3-(2-methoxybenzyl)-7-pentyl-2H-chromen-2-one (21a, PSB-SB-1202), a dual CB(1)/CB(2)agonist (CB(1)K(i) 0.032 muM, EC(50) 0.056 muM; CB(2)K(i) 0.049 muM, EC(50) 0.014 muM), 5-hydroxy-3-(2-hydroxybenzyl)-7-(2-methyloct-2-yl)-2H-chromen-2-one (25b, PSB-SB-1203), a dual CB(1)/CB(2) ligand that blocks CB(1) but activates CB(2) receptors (CB(1)K(i) 0.244 muM; CB(2)K(i) 0.210 muM, EC(50) 0.054 muM), and 7-(1-butylcyclopentyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (27b, PSB-SB-1204), a selective CB(2) receptor agonist (CB(1)K(i) 1.59 muM; CB(2)K(i) 0.068 muM, EC(50) 0.048 muM).
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Rimonabant Cannabinoid receptor 1 Ki (nM) 12.6 N/A N/A Details