Synthesis, Receptor Affinity, and Antiallodynic Activity of Spirocyclic σ Receptor Ligands with Exocyclic Amino Moiety

In
order to detect novel σ receptor ligands, the rigid spiro[[2]­benzopyran-1,1′-cyclohexan]-4′-one
was connected with amino moieties derived from σ2 receptor preferring lead compounds resulting in mixtures of trans- and cis-configured amines 6, 18, and 27. In a four step synthesis
the methyl acetals 6 were converted into fluoroethyl
derivatives 13 and 30. The most promising
σ2 receptor ligand is the methyl acetal 6a bearing a 2,4-dimethyl­benzylamino moiety. The fluoroethyl
derivatives 13c and 13d reveal high σ1 affinity but moderate selectivity over the σ2 subtype. In mice 13c and 13d showed antiallodynic
activity that is stronger than that of the reference σ1 antagonist BD-1063 (34). Since the antiallodynic activity
of 13c could only be partially reversed by the σ1 agonist PRE-084 (35), it is postulated that
a second mechanism contributes to its overall antiallodynic effect.
In contrast, the antiallodynic effect of its diastereomer 13d can be totally explained by a σ1 antagonism.