2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.

2 '-C-methyl analogues of selective adenosine receptor agonists: Synthesis and binding studies

TRINCAVELLI, MARIA LETIZIA;MARTINI, CLAUDIA;MAZZONI, MARIA ROSA;LUCACCHINI, ANTONIO;
1998

Abstract

2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.
Franchetti, P; Cappellacci, L; Marchetti, S; Trincavelli, MARIA LETIZIA; Martini, Claudia; Mazzoni, MARIA ROSA; Lucacchini, Antonio; Grifantini, M.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/176636
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 66
social impact