SPIROPIPERIDINES AS HIGH-AFFINITY, SELECTIVE SIGMA-LIGANDS

A variety of achiral conformationally restricted spirocyclic piperidines have been prepared in an attempt to investigate the functional role of the central sigma-recognition site. All the compounds possessed a lipophilic N-substituent incorporating either a tetralin, indan, or benzocycloheptane skeleton. Their in vitro affinity at the sigma-site was assessed in radioligand displacement experiments with guinea pig cerebellum homogenates using the sigma-specific radioligand [H-3]-N,N'-di-o-tolyguanidine ([H-3]-DTG, [H-3]-6). A study of the structure-activity relationships identified the N-butyl and N-dimethylallyl substituents as the optimum groups for high affinity and selectivity at the sigma-site (e.g., 3,4-dihydro-1'-(3-methylbut-2-enyl)spiro[1H-indene-1,4'-piperidine] (48), pIC50 = 8.9 vs [3H]-6 and greater than 10000-fold selective over the dopamine D2 receptor). Such compounds are amongst the highest affinity sigma-ligands reported to date, with excellent selectivity over the dopamine D2 receptor, and may serve as at useful tool for exploring the physiological role of the sigma-site.