Synthesis and structure–affinity relationships of novel spirocyclic σ receptor ligands with furopyrazole structure

The synthesis of novel spirocyclic σ receptor ligands with high affinity is described. The cyclization of the hydroxy acetal 8, which represents a key step in the synthesis of the spirocyclic compounds 3, was supported by theoretical considerations. The affinity of the spirocyclic furopyrazoles 3a–c to the σ receptors was determined in receptor binding studies with radioligands. The N-benzyl (3b) and N-butyl (3c) derivatives display very high σ1 receptor affinity (3b, Ki = 0.50 nM; 3c, Ki = 1.28 nM) and high selectivity toward the σ2 receptor and some other receptor systems. Calculation of crucial distances of the spirocyclic furopyrazole derivatives 3b and 3c shows good correlation with the pharmacophore model of Glennon.

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