7-Alkyl-3-benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists.
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 μM), 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 μM, EC(50) 0.056 μM; CB(2)K(i) 0.049 μM, EC(50) 0.014 μM), 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 μM; CB(2)K(i) 0.210 μM, EC(50) 0.054 μM), 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 μM; CB(2)K(i) 0.068 μM, EC(50) 0.048 μM).
Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Viktor
V
Rempel
Nicole
N
Volz
Sonja
S
Hinz
Tadeusz
T
Karcz
Irene
I
Meliciani
Martin
M
Nieger
Wolfgang
W
Wenzel
Stefan
S
Bräse
Christa E
CE
Müller
D000818:Animals; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003374:Coumarins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2