%0 Journal Article %1 Cappellacci2008 %A Cappellacci, L. %A Franchetti, P. %A Vita, P. %A Petrelli, R. %A Lavecchia, A. %A Costa, B. %A Spinetti, F. %A Martini, C. %A Klotz, K. N. %A Grifantini, M. %D 2008 %J Bioorg Med Chem %K A1/*agonists Adenosine Animals Binding Carbamates/*chemistry Computer Electricity Humans Hydrophobicity Models, Molecular Nucleosides/*chemistry/*pharmacology Protein Purine Relationship Simulation Static Structure-Activity Swine Receptor %N 1 %P 336-53 %T 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 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17933541 %V 16 %X 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)-tetrahydrofuranyladenosine (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).

@article{Cappellacci2008, abstract = {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).}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Cappellacci, L. and Franchetti, P. and Vita, P. and Petrelli, R. and Lavecchia, A. and Costa, B. and Spinetti, F. and Martini, C. and Klotz, K. N. and Grifantini, M.}, biburl = {https://www.bibsonomy.org/bibtex/25ca85cda2f60edae818ce440e0bbf634/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {874e54907c5695d3e272b695e4ea2794}, intrahash = {5ca85cda2f60edae818ce440e0bbf634}, issn = {1464-3391 (Electronic) 1464-3391 (Linking)}, journal = {Bioorg Med Chem}, keywords = {A1/*agonists Adenosine Animals Binding Carbamates/*chemistry Computer Electricity Humans Hydrophobicity Models, Molecular Nucleosides/*chemistry/*pharmacology Protein Purine Relationship Simulation Static Structure-Activity Swine Receptor}, month = {Jan 1}, note = {Cappellacci, Loredana Franchetti, Palmarisa Vita, Patrizia Petrelli, Riccardo Lavecchia, Antonio Costa, Barbara Spinetti, Francesca Martini, Claudia Klotz, Karl-Norbert Grifantini, Mario Research Support, Non-U.S. Gov't England Bioorganic \& medicinal chemistry Bioorg Med Chem. 2008 Jan 1;16(1):336-53. Epub 2007 Sep 22.}, number = 1, pages = {336-53}, shorttitle = {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}, timestamp = {2010-12-14T18:22:02.000+0100}, title = {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}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17933541}, volume = 16, year = 2008 }