title: Novel sigma receptor ligands: synthesis and biological profile.
abstract: The aim of the present study was to investigate the biological profile of new substituted 1-phenyl-2-cyclopropylmethylamines. High affinity for both sigma subtypes was achieved when 4-phenylpiperidin-4-ol (4a-e) and 4-benzylpiperidine moieties were present (5a-e). (1R,2S/1S,2R)-2-[4-Hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate (4b) showed high affinity for the sigma1 sites (Ki = 1.5 nM) and the most favorable sigma1/sigma2 selectivity (Ki(sigma2)/Ki(sigma1) = 33.9). Binding affinity studies showed that 4b binding on N-methyl-d-aspartate (NMDA), dopaminergic (D1, D2, D3), muscarinic, histaminergic H1, adrenergic (alpha1, alpha2), serotoninergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT6), DA (DAT), and 5-HT (SERT) transporters was not significant. Interestingly, sigma ligands differently induced the expression of tissue transglutaminase (TG-2) in primary astroglial cell cultures. We suggest that 4b may act as a sigma1/sigma2 agonist and that the sigma ligands may modulate TG-2 differently.
authors.affiliation: Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Agata
authors.initials: A
authors.lastname: Campisi
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.forename: Giovanni
authors.initials: G
authors.lastname: Li Volti
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bramanti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannavò
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ientile
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronsisvalle
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053938:DNA Fragmentation; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000096:biosynthesis
chemical_list: D003521:Cyclopropanes; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; C518986:methyl 2-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)-1-(4-methylphenyl)cyclopropanecarboxylate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D053148:Caspase 3; D019204:GTP-Binding Proteins