5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: affinity, efficacy, and selectivity for A1 receptor from different species.
A series of 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-C-methyl analogues of the A(1) adenosine receptor (A(1)AR) full agonists N(6)-cyclopentyladenosine (CPA), 2-chloro-N(6)-cyclopentyladenosine (CCPA), N(6)-[3-(R)-tetrahydrofuranyl]adenosine (tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized and evaluated for their affinity for adenosine receptor subtypes from bovine, porcine, and human species. In the N(6)-cyclopentylamino series, the 5'-substituted derivatives showed a reduced affinity at the bovine A(1)AR compared to the parent compounds; however, the selectivity for A(1) versus A(2A) receptor was retained or increased. The corresponding N(6)-3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine A(1)AR. The 5'-methylthionocarbamoyl derivative of 2'-Me-CCPA showed the best affinity at porcine A(1)AR with a K(i) value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3- to 5-fold lower affinity at A(1)AR and very low affinity at the other subtypes (A(2A), A(2B), and A(3)) compared to the corresponding N(6)-cyclopentyl analogues. The 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were found to be partial A(1) agonists at the porcine receptor. Docking studies explained the lower affinity of N(6)-3-(R)-tetrahydrofuranyl-substituted compounds at bovine A(1)AR compared to that of N(6)-cyclopentyl analogues, showing that the oxygen of the tetrahydrofuranyl ring establishes unfavorable electrostatic interactions with the CO oxygen of Asn254. The low binding affinity of the 2'-C-methyl-N(6)-3-(R)-tetrahydrofuranyl adenosine analogues at human A(1)AR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7).
Cappellacci
Loredana
L
Dipartimento di Scienze Chimiche, Università di Camerino, 62032 Camerino, Italy.
Franchetti
Palmarisa
P
Vita
Patrizia
P
Petrelli
Riccardo
R
Lavecchia
Antonio
A
Costa
Barbara
B
Spinetti
Francesca
F
Martini
Claudia
C
Klotz
Karl-Norbert
KN
Grifantini
Mario
M
D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D002219:Carbamates / Q000737:chemistry*; D002417:Cattle; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D011684:Purine Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013552:Swine
D058907:Adenosine A1 Receptor Agonists; D002219:Carbamates; D011684:Purine Nucleosides