From tyrosine to glycine: synthesis and biological activity of potent antagonists of the purinergic P2X7 receptor.
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.
Romagnoli
Romeo
R
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Ferrara, Italy. rmr@unife.it
Baraldi
Pier Giovanni
PG
Carrion
Maria Dora
MD
Cara
Carlota Lopez
CL
Preti
Delia
D
Cruz-Lopez
Olga
O
Tabrizi
Mojgan Aghazadeh
MA
Moorman
Allan R
AR
Gessi
Stefania
S
Fogli
Eleonora
E
Sacchetto
Valeria
V
Borea
Pier Andrea
PA
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
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