Synthesis and pharmacological evaluation of 6-piperidino- and 6-piperazinoalkyl-2(3H)-benzothiazolones as mixed σ/5-HT1A ligands

In an effort to produce new pharmacological probes with mixed σ/5-HT1A affinity, we have synthesized a series of 12 original 6-piperidino- or piperazino-alkyl-2(3H)-benzothiazolones and their receptor binding profile (σ, 5-HT1A, 5-HT2A, 5-HT3, D2, H1, and M1) was determined. The best mixed σ/5-HT1A affinity profile was found within the piperidine series with 4-benzyl substitution associated to linker methylene chain n=2 (Ki 5 and 4 nM, respectively). Moreover, a highly selective σ2 ligand was obtained with a 3,4-dichlorobenzyl substitution associated to n=4 (Ki 2 nM, selectivity ratio σ1/σ2=70).