%0 Journal Article %1 Cappellacci2005 %A Cappellacci, L. %A Franchetti, P. %A Pasqualini, M. %A Petrelli, R. %A Vita, P. %A Lavecchia, A. %A Novellino, E. %A Costa, B. %A Martini, C. %A Klotz, K. N. %A Grifantini, M. %D 2005 %J J Med Chem %K & Adenosine/*analogs Adenylate Animals Assay Binding, Brain/metabolism CHO Competitive Cricetinae Cricetulus Cyclase/antagonists Humans Models, Molecular P1/*agonists/chemistry Purinergic Radioligand Rats Ribose/*chemistry derivatives/*chemical inhibitors synthesis/pharmacology Receptor Cell %N 5 %P 1550-62 %T Synthesis, biological evaluation, and molecular modeling of ribose-modified adenosine analogues as adenosine receptor agonists %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15743197 %V 48 %X A number of 3'-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2'-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A(1), A(2A), and A(3) receptors in bovine brain membranes showed that the 3'-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N(6)-substitution with groups that induce high potency and selectivity at A(1) receptor, the affinity and selectivity were increased. However, all 3'-C-methyl derivatives proved to be very less active than the corresponding 2'-C-methyl analogues. The most active compound was found to be 3'-Me-CPA which displayed a K(i) value of 0.35 microM at A(1) receptor and a selectivity for A(1) vs A(2A) and A(3) receptors higher than 28-fold. 2'-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A(1) receptor with a K(i) value of 3.3 nM and 2903- and 341-fold selective vs human A(2A) and A(3) receptors, respectively. In functional assay, 3'-Me-CPA, 3'-Me-CCPA, and 2-Cl-3'-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC(50) values ranging from 0.3 to 4.9 microM, acting as full agonists. A rhodopsin-based model of the bovine A(1)AR was built to rationalize the higher affinity and selectivity of 2'-C-methyl derivatives of N(6)-substituted-adenosine compared to that of 3'-C-methyl analogues. In the docking exploration, it was found that 2'-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA(1)AR which were not preserved in the molecular dynamics simulation of 3'-Me-CCPA/bA(1)AR complex.

@article{Cappellacci2005, abstract = {A number of 3'-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2'-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A(1), A(2A), and A(3) receptors in bovine brain membranes showed that the 3'-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N(6)-substitution with groups that induce high potency and selectivity at A(1) receptor, the affinity and selectivity were increased. However, all 3'-C-methyl derivatives proved to be very less active than the corresponding 2'-C-methyl analogues. The most active compound was found to be 3'-Me-CPA which displayed a K(i) value of 0.35 microM at A(1) receptor and a selectivity for A(1) vs A(2A) and A(3) receptors higher than 28-fold. 2'-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A(1) receptor with a K(i) value of 3.3 nM and 2903- and 341-fold selective vs human A(2A) and A(3) receptors, respectively. In functional assay, 3'-Me-CPA, 3'-Me-CCPA, and 2-Cl-3'-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC(50) values ranging from 0.3 to 4.9 microM, acting as full agonists. A rhodopsin-based model of the bovine A(1)AR was built to rationalize the higher affinity and selectivity of 2'-C-methyl derivatives of N(6)-substituted-adenosine compared to that of 3'-C-methyl analogues. In the docking exploration, it was found that 2'-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA(1)AR which were not preserved in the molecular dynamics simulation of 3'-Me-CCPA/bA(1)AR complex.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Cappellacci, L. and Franchetti, P. and Pasqualini, M. and Petrelli, R. and Vita, P. and Lavecchia, A. and Novellino, E. and Costa, B. and Martini, C. and Klotz, K. N. and Grifantini, M.}, biburl = {https://www.bibsonomy.org/bibtex/24a2fb6a291818b6882e8daf28f958244/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {1644eb746812928d19065709eb4fd5ff}, intrahash = {4a2fb6a291818b6882e8daf28f958244}, issn = {0022-2623 (Print) 0022-2623 (Linking)}, journal = {J Med Chem}, keywords = {& Adenosine/*analogs Adenylate Animals Assay Binding, Brain/metabolism CHO Competitive Cricetinae Cricetulus Cyclase/antagonists Humans Models, Molecular P1/*agonists/chemistry Purinergic Radioligand Rats Ribose/*chemistry derivatives/*chemical inhibitors synthesis/pharmacology Receptor Cell}, month = {Mar 10}, note = {Cappellacci, Loredana Franchetti, Palmarisa Pasqualini, Michela Petrelli, Riccardo Vita, Patrizia Lavecchia, Antonio Novellino, Ettore Costa, Barbara Martini, Claudia Klotz, Karl-Norbert Grifantini, Mario In Vitro Research Support, Non-U.S. Gov't United States Journal of medicinal chemistry J Med Chem. 2005 Mar 10;48(5):1550-62.}, number = 5, pages = {1550-62}, shorttitle = {Synthesis, biological evaluation, and molecular modeling of ribose-modified adenosine analogues as adenosine receptor agonists}, timestamp = {2010-12-14T18:22:02.000+0100}, title = {Synthesis, biological evaluation, and molecular modeling of ribose-modified adenosine analogues as adenosine receptor agonists}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15743197}, volume = 48, year = 2005 }