7-Alkyl-3-benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists.

Article Details

Citation

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).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
RimonabantCannabinoid receptor 1Ki (nM)12.6N/AN/ADetails