title: From tyrosine to glycine: synthesis and biological activity of potent antagonists of the purinergic P2X7 receptor.
abstract: The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a "druglike" profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, the present study was designed to evaluate the functional antagonistic properties of a novel series of glycine derivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X7 receptor. The most potent P2X7 receptor antagonist identified in this study (compound 4g) contains an o-fluorine substituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigated were ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Ferrara, Italy. rmr@unife.it
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Maria Dora
authors.initials: MD
authors.lastname: Carrion
authors.forename: Carlota Lopez
authors.initials: CL
authors.lastname: Cara
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fogli
authors.forename: Valeria
authors.initials: V
authors.lastname: Sacchetto
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D004996:Ethidium / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology; D014443:Tyrosine / Q000737:chemistry*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D005456:Fluorescent Dyes; D007546:Isoquinolines; D009281:Naphthalenes; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D013449:Sulfonamides; D013450:Sulfones; C523426:isoquinolinesulfon-5-yl-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-oxoethyl)amide; D015091:beta-Alanine; D014443:Tyrosine; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D004996:Ethidium; D002118:Calcium; D005998:Glycine