Exploitation of an additional hydrophobic pocket of σ ₁ receptors: Late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization

The hypothesis that the σ ₁ receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ ₁ receptor 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 σ ₁ receptor protein. The catalyst system PdCl ₂/2,2′-bipyridyl/Ag ₂CO ₃ 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 σ ₁ affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ ₁ affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ ₁ receptor 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 σ ₁ receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ ₁ affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ ₁ affinity. However, decrease of σ ₁ 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 σ ₁ receptor.