1-Phenyl-3azabicyclo[3.1.0]hexane derivatives as new ligands for sigma receptors

A series of 1-phenyl-3-azabicyclo[3.1.0]hexanes were synthesized as more conformationally restricted prototypical σ ligands 3-phenylpiperidines with the aim to developing new σ ligands. Compared with 3-phenylpiperidines reported by Largent et al., binding data showed that conformational restriction was not detrimental for σ receptor affinity. Specifically, except for secondary amine 4, all racemic 1-phenyl-3-azabicyclo[3.1.0]hexane derivatives (12-19) showed moderate to high affinity for both σ1 and σ2 receptors. Dextrorotatory isomers with the same configuration of 3-phenylpiperidines to C-1 carbon linked to the phenyl ring showed a better affinity and selectivity for σ1 receptors compared to the respective levorotatory isomers. Compounds (+)-14 and (+)-15 displayed very high affinity for σ1 (Ki = 0.9 and 2.3 nM respectively) but low selectivity for receptor subtypes. Compound (+)-18 with N-phenethyl substituent embodies the highest selectivity for σ1 receptors.