Characterization of the biochemical effects of new 1, 8-naphthyridine derivatives, beta-receptor antagonists, in ventricular myocytes.
Novel derivatives of 1, 8-naphthyridine were synthesized from 7-amino-2-hydroxy-4-morpholinomethyl-1, 8-naphthyridine. The ability of the synthesized compounds to inhibit isoproterenol(ISO)-induced phosphorylation of phospholamban (PLB) was assessed. Their ability to block both beta(1) and beta(2) receptors almost completely abolished all ISO effects on phosphorylation of PLB. Analogues with either a 7-hydroxy-2-N-ethoxycarbonylpiperazine or a 7-hydroxy-2-piperazine substituent, designated as 6 and 9 respectively, showed a higher affinity for beta(1) receptor than that of the methoxy derivatives 12 and 13. However, treatment with 30 microM 9 and 1mM 13 lead to comparable levels of PLB phosphorylation. The reduction to 6-amino derivatives 10 and 17 led to compounds possessing beta(2) receptor blocking properties. The ability of the synthesized compounds to inhibit forskolin-stimulated cAMP production was also studied. Together, these results suggest that the 1, 8-naphthyridine parent structure can be modified, to produce compounds with increased activity whose effect in rat appears to be more clearly related to antagonism of beta(1)-rather than beta(2)-adrenergic receptors.
Al jamal
Jalal A
JA
Faculty of Pharmacy, Philadelphia University, Amman, Jordan. jaljamal@philadelphia.edu.jo
Badawneh
Muwaffag
M
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D013329:Structure-Activity Relationship; D000099211:Phospholamban
D000319:Adrenergic beta-Antagonists; D002135:Calcium-Binding Proteins; D009287:Naphthyridines; D000099211:Phospholamban