New Piperazine Derivatives of 6-Acetyl-7-hydroxy-4-methylcoumarin as 5-HT1A Receptor Agents

A series of 15 new derivatives of 6-acetyl-7-hydroxy-4-methylcoumarin containing a piperazine group were designed with the help of computational methods and were synthesized to study their affinity for the serotonin 5-HT1A and 5-HT2A receptors. Among them, 6-acetyl-7-{4-[4-(3-bromophenyl)piperazin-1-yl]butoxy}-4-methylchromen-2-one (4) and 6-acetyl-7-{4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy}-4-methylchromen-2-one (7) exhibited excellent activity for 5-HT1A receptors with Ki values 0.78 (0.4-1.4) nM and 0.57 (0.2-1.3) nM, respectively, comparable to the Ki values of 8-OH-DPAT (0.25 (0.097-0.66) nM). The equilibrium dissociation constant values of the tested compounds showed differential intrinsic activities of the agonist and antagonist modes.

Automated summary

A series of piperazine-containing derivatives of 6-acetyl-7-hydroxy-4-methylcoumarin were designed and synthesized to study their affinity for serotonin receptors. Compounds 4 and 7 exhibited excellent activity for 5-HT1A receptors with Ki values comparable to 8-OH-DPAT. The tested compounds showed differential intrinsic activities in agonist and antagonist modes.