title: Combination of two pharmacophoric systems: synthesis and pharmacological evaluation of spirocyclic pyranopyrazoles with high σ₁ receptor affinity.
abstract: The novel class of spirocyclic σ(1) ligands 3 (6',7'-dihydro-1'H-spiro[piperidine-4,4'-pyrano[4,3-c]pyrazoles]) was designed by the combination of the potent σ(1) ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1', 1, and 6'. Whereas the small electron rich methylpyrazole heterocycle was less tolerated by the σ(1) receptor protein, the introduction of a phenyl substituent instead of the methyl group led to ligands with a high σ(1) affinity. It is postulated that the additional phenyl substituent occupies a previously unrecognized hydrophobic region of the σ(1) receptor resulting in additional lipophilic interactions. The spirocyclic pyranopyrazoles are very selective against the σ(2) subtype, the PCP binding site of the NMDA receptor, and further targets. Despite high σ(1) affinity, the cyclohexylmethyl derivative 17i (K(i) (σ(1)) = 0.55 nM) and the isopentenyl derivative 17p (K(i) (σ(1)) = 1.6 nM) showed only low antiallodynic activity in the capsaicin assay.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der 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: Kirstin
authors.initials: K
authors.lastname: Lehmkuhl
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000188:drug therapy; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D051379:Mice; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014110:Touch
chemical_list: D000700:Analgesics; D011714:Pyrans; D011720:Pyrazoles; D017465:Receptors, Opioid, delta; D013141:Spiro Compounds