The development of diazabicyclo[4.3.0]nonane and 2,7-diazaspiro[3.5]nonane
derivatives as sigma receptors (SRs) ligands is reported. The compounds
were evaluated in S1R and S2R binding assays, and modeling studies
were carried out to analyze the binding mode. The most notable compounds,4b(AD186,KiS1R = 2.7 nM,KiS2R = 27 nM),5b(AB21,KiS1R = 13 nM,KiS2R = 102 nM), and8f(AB10,KiS1R = 10 nM,KiS2R = 165 nM),
have been screened for analgesic effectsin vivo,
and their functional profile was determined throughin vivoandin vitromodels. Compounds5band8freached the maximum antiallodynic effect at 20 mg/kg. The
selective S1R agonist PRE-084 completely reversed their action, indicating
that the effects are entirely dependent on the S1R antagonism. Conversely,
compound4bsharing the 2,7-diazaspiro[3.5]nonane core
as5bwas completely devoid of antiallodynic effect.
Interestingly, compound4bfully reversed the antiallodynic
effect of BD-1063, indicating that4binduces an S1R
agonisticin vivoeffect. The functional profiles
were confirmed by the phenytoin assay. Our study might establish the
importance of 2,7-diazaspiro[3.5]nonane core for the development of
S1R compounds with specific agonist or antagonist profile and the
role of the diazabicyclo[4.3.0]nonane in the development of novel
SR ligands.