title: Design, synthesis and pharmacological evaluation of spirocyclic σ(1) receptor ligands with exocyclic amino moiety (increased distance 1).
abstract: Various pharmacophore models for potent σ(1) ligands specify a basic amino group flanked by two different hydrophobic regions in defined distances to the basic amine (distance 1 and distance 2, respectively). According to these models distance 1 of the potent spirocyclic σ(1) ligand 1 is too short. In order to find a new class of more potent σ(1) ligands and to verify the distance hypothesis of the pharmacophore models spirocyclic compounds 2 with an exocyclic amino group were designed and synthesized. The secondary amines 8 and 9 with N-benzyl residues are >100-fold less potent than the spirocyclic piperidine 1. However, the tertiary methylamines trans-11 and cis-11 represent potent σ(1) ligands with K(i)-values of 43 and 24 nM, respectively. Whereas one large benzyl moiety is required for high σ(1) receptor binding, a second large N-substituent is not tolerated by the σ(1) receptor protein. As a rule, cis-configured diastereomers with a longer distance 1 (predominantly 7.16-7.23 Å) show higher σ(1) affinities than their trans-configured counterparts (distance 1 is predominantly 5.88-6.26 Å).
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rack
authors.forename: Roland
authors.initials: R
authors.lastname: Fröhlich
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D008024:Ligands; D017480:Receptors, sigma; D013141:Spiro Compounds