Spiropiperidines as high-affinity, selective σ ligands

Article abstract of DOI:10.1021/jm00089a013

A variety of achiral conformationally restricted spirocyclic piperidines have been prepared in an attempt to investigate the functional role of the central σ recognition site. All the compounds possessed a lipophilic N- substituent incorporating either a tetralin, indan, or benzocycloheptane skeleton. Their in vitro affinity at the σ site was assessed in radioligand displacement experiments with guinea pig cerebellum homogenates using the σ- specific radioligand [³H]-N,N'-di-o-tolylguanidine ([³H]-DTG, [³H]-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 σ 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 10 000-fold selective over the dopamine D₂ receptor). Such compounds are amongst the highest affinity σ ligands reported to date, with excellent selectivity over the dopamine D₂ receptor, and may serve as a useful tool for exploring the physiological role of the σ site.