Exploitation of an additional hydrophobic pocket of σ₁ receptors: Late-stage diverse modifications of spirocyclic thiophenes by C–H bond functionalization

The hypothesis that the σ₁receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ₁receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the σ₁receptor protein. The catalyst system PdCl₂/2,2′-bipyridyl/Ag₂CO₃ is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ₁ affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ₁ affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ₁receptor ligands (3a: K_i = 4.5 nM; 4a: K_i = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ₁receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ₁ affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ₁ affinity. However, decrease of σ₁ affinity by extension of the π-system to a biphenylyl substituent (4j: K_i = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the σ₁receptor.