title: Novel highly potent and selective sigma 1 receptor antagonists related to spipethiane.
abstract: Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novel potent sigma(1) ligands. sigma(1) affinity and sigma(1/)sigma(2) selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing sigma(1) receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the sigma(1) antagonist profile of this series of compounds. In particular, due to its high sigma(1) affinity (pK(i) = 10.28) and sigma(1)/sigma(2) selectivity ratio (29510), compound 9 might be a novel valuable tool for sigma receptor characterization and a suitable template for the rational design of potential therapeutically useful sigma(1) antagonists.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.forename: Laura
authors.initials: L
authors.lastname: Mattioli
authors.forename: Maura
authors.initials: M
authors.lastname: Palmery
authors.forename: Marina
authors.initials: M
authors.lastname: Perfumi
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Tucci
authors.forename: Margherita
authors.initials: M
authors.lastname: Zotti
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000187:drug effects; D019169:Jurkat Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010147:Pain Measurement; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D000970:Antineoplastic Agents; D010880:Piperidines; D017480:Receptors, sigma; D013141:Spiro Compounds; D000097605:Sigma-1 Receptor; C112093:spipethiane