title: Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure.
abstract: The synthesis of novel spirocyclic sigma 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 sigma receptors was determined in receptor binding studies with radioligands. The N-benzyl (3b) and N-butyl (3c) derivatives display very high sigma(1) receptor affinity (3b, K(i)=0.50 nM; 3c, K(i)=1.28 nM) and high selectivity toward the sigma(2) 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schläger
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Ernst-Ulrich
authors.initials: EU
authors.lastname: Würthwein
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D003500:Cyclization; D008024:Ligands; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011720:Pyrazoles; D017480:Receptors, sigma; D013141:Spiro Compounds