Synthesis and structure-affinity relationships of 1-[ω-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones as 5-HT7 receptor ligands

Article abstract of DOI:10.1021/jm020994z

Structural requirements for 5-HT₇ receptor affinity and selectivity over that for the 5-HT_1A receptor were studied on a series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones. The presence of a hydroxy or methoxy substituent on aryl ketone moiety, alkyl chain length, and the nature of N-1-piperazine substituent were explored. 6-[4-(3-Benzisoxazolyl)-1-piperazinyl]-1-(2-hydroxyphenyl)-1-hexanone (40) and its methoxy analogue 43 exhibited high 5-HT₇ receptor affinities (K_i = 2.93 nM and 0.90 nM, respectively) and agonist properties when tested for 5-HT₇ receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.