title: Exploitation of an additional hydrophobic pocket of σ1 receptors: late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization.
abstract: 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(2)CO(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.
authors: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
authors: Christina
authors: C
authors: Meyer
authors: Benedikt
authors: B
authors: Neue
authors: Dirk
authors: D
authors: Schepmann
authors: Shuichi
authors: S
authors: Yanagisawa
authors: Junichiro
authors: J
authors: Yamaguchi
authors: Ernst-Ulrich
authors: EU
authors: Würthwein
authors: Kenichiro
authors: K
authors: Itami
authors: Bernhard
authors: B
authors: Wünsch
mesh_terms: D002244:Carbon / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013141:Spiro Compounds / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D008024:Ligands; D013141:Spiro Compounds; D013876:Thiophenes; D002244:Carbon; D006859:Hydrogen