A review of studies done by the authors and others. Adenosine is an endogenous modulator of a large variety of physiol. functions through the interaction with specific cell membrane G-protein-coupled receptors classified as A1, A2A, A2B, and A3. Activation of A3 receptors has been shown to stimulate phospholipase C and to inhibit adenylate cyclase. A3 agonists also cause stimulation of phospholipase D and the release of inflammatory mediators, such as histamine from mast cells, which are responsible for inflammation and hypotension. For these reasons, the clin. use of A3 adenosine receptors antagonists for the treatment of asthma and inflammatory disease has been suggested. Recent studies also indicated a possible employment of these derivs. as antitumor agents. Different classes of polyheterocyclic compds. have been identified as potent A3 antagonists. Herein, we report our past and recent results in the development of tricyclic A3 selective antagonists. The pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus has esp. been investigated by our group. Our interests were focused on the effects of substitution of the Ph ring of the arylcarbamoyl moiety at N5 position and of substituents at C9 and/or at N8 pyrazole nitrogen. These studies allowed us to obtain a large variety of compds. which showed affinities in the nanomolar range with human A3 adenosine receptors with a high degree of selectivity vs. all other receptors subtypes. Thanks to the introduction of alkylating groups at p-position of the N5-phenylcarbamoyl chain, we succeeded in realizing potent irreversible A3 adenosine antagonists. Finally, the replacement of the Ph nucleus of carbamoyl function with a pyridine ring conferred water soly. to the corresponding derivs., which are also characterized by high levels of A3 affinity and selectivity.
Recent developments in the field of A(3) adenosine receptor antagonists
BARALDI, Pier Giovanni;AGHAZADEH TABRIZI, Mojgan;FRUTTAROLO, Francesca;PRETI, Delia;ROMAGNOLI, Romeo;MERIGHI, Stefania;GESSI, Stefania;VARANI, Katia;BOREA, Pier Andrea
2003
Abstract
A review of studies done by the authors and others. Adenosine is an endogenous modulator of a large variety of physiol. functions through the interaction with specific cell membrane G-protein-coupled receptors classified as A1, A2A, A2B, and A3. Activation of A3 receptors has been shown to stimulate phospholipase C and to inhibit adenylate cyclase. A3 agonists also cause stimulation of phospholipase D and the release of inflammatory mediators, such as histamine from mast cells, which are responsible for inflammation and hypotension. For these reasons, the clin. use of A3 adenosine receptors antagonists for the treatment of asthma and inflammatory disease has been suggested. Recent studies also indicated a possible employment of these derivs. as antitumor agents. Different classes of polyheterocyclic compds. have been identified as potent A3 antagonists. Herein, we report our past and recent results in the development of tricyclic A3 selective antagonists. The pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus has esp. been investigated by our group. Our interests were focused on the effects of substitution of the Ph ring of the arylcarbamoyl moiety at N5 position and of substituents at C9 and/or at N8 pyrazole nitrogen. These studies allowed us to obtain a large variety of compds. which showed affinities in the nanomolar range with human A3 adenosine receptors with a high degree of selectivity vs. all other receptors subtypes. Thanks to the introduction of alkylating groups at p-position of the N5-phenylcarbamoyl chain, we succeeded in realizing potent irreversible A3 adenosine antagonists. Finally, the replacement of the Ph nucleus of carbamoyl function with a pyridine ring conferred water soly. to the corresponding derivs., which are also characterized by high levels of A3 affinity and selectivity.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
