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-HT1A 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-HT1A 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 structureactivity relationship was visible only for the interaction of the compounds with the 5-HT7 receptor, which strongly favored flexible analogs.