Adenosine mediates its pysiological effects through four G protein-coupled receptors (A1, A2A, A2B and A3). A large number of agonists with high affinity at A1, A2A, A3 adenosine receptors and moderate affinity at A2B receptor have been developed over the years. Many compounds originally thought to be selective for the A1 or A2A subtypes later turned to be also potent agonists at more recently discovered A3 receptor. Owing to he great interest in A1 agonists as neuroprotective, antilipolytic, antiarrhythmic, and antinociceptive agents, there is a need for novel agonists with high potency and selectivity at this receptor subtype to avoid side effects due to the stimulation of the other subtypes. We discovered that the substitution of the hydrogen in 2'-position of the ribose moiety of the A1 selective agonist CCPA with a methyl group (2'-Me-CCPA) reduces the affinity at human A2A and A3 receptors, thus increasing the selectivity for A1 subtype [1]. In this communication we report on the affinity at human adenosine receptors of 2'-C-methyl derivatives of Tecadenoson (CVT510, N6-3(R)-tetrahydrofuranyl-adenosine), a potent and selective A1 agonist in clinical trials for treatment of supraventricular tachyarrhythmias, and of its 2-chloro derivatives (2-Cl-Tecadenoson). Tecadenosn, 2-Cl-Tecadenoson and their 2'-C-methyl derivatives were evaluated for the affinity at human A1, A2A, A2B, and A3 ARs expressed in CHO cells in comparison with CPA, CCPA, 2'-Me-CPA and 2'-Me-CCPA. With the exception of Tecadenoson that proved to be equipotent to CPA, N6-3(R)-tetrahydrofuranyl substituted derivatives showed only 2.5- to 5-fold less affinity at human A1 AR in comparison with the corresponding N6-cyclopentyl analogues. It was further confirmed that the introduction of a methyl group in the 2'-position of the ribose moiety of adenosine analogues induces a relevant decrease of affinity at A2A and A3 receptors. Thus, 2'-Me-Tecadenoson and 2'-Me-2-Cl-Tecadenoson turned out to be very selective compounds for human A1AR (> 4,762- to > 6,452-fold vs human A2A and 211- to 288-fold vs A3 receptor, respectively) [1] Cappellacci L et al J Med Chem 2005, 48, 1550-62

2’-C-Methyl derivatives of tecadenoson and 2-chloro-tecadenoson with increased selectivity for human A1 adenosine receptor

CAPPELLACCI, Loredana;FRANCHETTI, Palmarisa;VITA, PATRIZIA;PETRELLI, Riccardo;GRIFANTINI, Mario
2006

Abstract

Adenosine mediates its pysiological effects through four G protein-coupled receptors (A1, A2A, A2B and A3). A large number of agonists with high affinity at A1, A2A, A3 adenosine receptors and moderate affinity at A2B receptor have been developed over the years. Many compounds originally thought to be selective for the A1 or A2A subtypes later turned to be also potent agonists at more recently discovered A3 receptor. Owing to he great interest in A1 agonists as neuroprotective, antilipolytic, antiarrhythmic, and antinociceptive agents, there is a need for novel agonists with high potency and selectivity at this receptor subtype to avoid side effects due to the stimulation of the other subtypes. We discovered that the substitution of the hydrogen in 2'-position of the ribose moiety of the A1 selective agonist CCPA with a methyl group (2'-Me-CCPA) reduces the affinity at human A2A and A3 receptors, thus increasing the selectivity for A1 subtype [1]. In this communication we report on the affinity at human adenosine receptors of 2'-C-methyl derivatives of Tecadenoson (CVT510, N6-3(R)-tetrahydrofuranyl-adenosine), a potent and selective A1 agonist in clinical trials for treatment of supraventricular tachyarrhythmias, and of its 2-chloro derivatives (2-Cl-Tecadenoson). Tecadenosn, 2-Cl-Tecadenoson and their 2'-C-methyl derivatives were evaluated for the affinity at human A1, A2A, A2B, and A3 ARs expressed in CHO cells in comparison with CPA, CCPA, 2'-Me-CPA and 2'-Me-CCPA. With the exception of Tecadenoson that proved to be equipotent to CPA, N6-3(R)-tetrahydrofuranyl substituted derivatives showed only 2.5- to 5-fold less affinity at human A1 AR in comparison with the corresponding N6-cyclopentyl analogues. It was further confirmed that the introduction of a methyl group in the 2'-position of the ribose moiety of adenosine analogues induces a relevant decrease of affinity at A2A and A3 receptors. Thus, 2'-Me-Tecadenoson and 2'-Me-2-Cl-Tecadenoson turned out to be very selective compounds for human A1AR (> 4,762- to > 6,452-fold vs human A2A and 211- to 288-fold vs A3 receptor, respectively) [1] Cappellacci L et al J Med Chem 2005, 48, 1550-62
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11581/108067
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