New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT1A/5‐HT7 Receptor Ligands

A series of new long‐chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5‐HT_1A and 5‐HT₇ receptor ligands. The compounds were prepared by a two‐step procedure using naphthalimide and 2H‐1,3‐benzoxazine‐2,4(3H)‐dione as imides, and 1‐(2‐methoxyphenyl)piperazine (o‐OMe‐PhP) and 1,2,3,4‐tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta‐ and hexamethylene chains as well as partly constrained m‐ and p‐xylyl moieties. In general, the new compounds were more active at the 5‐HT_1A than at the 5‐HT₇ receptor, and the o‐OMe‐PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o‐OMe‐PhP series, except for a small binding reduction for ligands containing the m‐xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure–activity relationship was visible only for the interaction of the compounds with the 5‐HT₇ receptor, which strongly favored flexible analogs.