A series of 7-alkyl-3-benzylcoumarins was designed, synthesized, and tested at cannabinoid CB₁ and CB₂ 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 CB₁ or CB₂ 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 CB₁antagonist (K_i CB₁ 0.022 μM), 5-methoxy-3-(2-methoxybenzyl)-7-pentyl-2H-chromen-2-one (21a, PSB-SB-1202), a dual CB₁/CB₂agonist (CB₁K_i 0.032 μM, EC₅₀ 0.056 μM; CB₂K_i 0.049 μM, EC₅₀ 0.014 μM), 5-hydroxy-3-(2-hydroxybenzyl)-7-(2-methyloct-2-yl)-2H-chromen-2-one (25b, PSB-SB-1203), a dual CB₁/CB₂ ligand that blocks CB₁ but activates CB₂ receptors (CB₁K_i 0.244 μM; CB₂K_i 0.210 μM, EC₅₀ 0.054 μM), and 7-(1-butylcyclopentyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (27b, PSB-SB-1204), a selective CB₂ receptor agonist (CB₁K_i 1.59 μM; CB₂K_i 0.068 μM, EC₅₀ 0.048 μM).