New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT 1A /5‐HT 7 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‐HT 7 receptor ligands. The compounds were prepared by a two‐step procedure using naphthalimide and 2 H‐ 1,3‐benzoxazine‐2,4(3 H )‐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‐HT 7 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‐HT 7 receptor, which strongly favored flexible analogs.