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

Abstract

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.