title: Thiophene bioisosteres of spirocyclic σ receptor ligands: relationships between substitution pattern and σ receptor affinity.
abstract: On the basis of the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 σ ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased σ(2) affinity and therefore to decreased σ(1)/σ(2) selectivity. Small substituents (e.g., OH, OCH(3), CN, CH(2)OH) in 6'-position adjacent to the O-atom were well tolerated by the σ(1) receptor. Removal of the substituent in 6'-position resulted in very potent but unselective σ ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of σ(1) affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the σ(1) affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the σ(1) affinity.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Oberdorf
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008024:Ligands; D010880:Piperidines; D011714:Pyrans; D017480:Receptors, sigma; D013141:Spiro Compounds; D013876:Thiophenes