Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists
P2Y 1 receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The presen...
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todo:paper_00222623_v43_n4_p746_Kim2023-10-03T14:30:13Z Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists Kim, Y.-C. Gallo-Rodriguez, C. Jang, S.-Y. Nandanan, E. Adams, M. Harden, T.K. Boyer, J.L. Jacobson, K.A. 2 [2 (2 chloro 6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) 2 [2 (6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) deoxyadenosine derivative ethylene derivative ganciclovir phospholipase C purine P2Y receptor purinergic receptor blocking agent receptor subtype unclassified drug animal cell article cis isomer controlled study drug potency drug receptor binding drug structure drug synthesis enzyme activation nonhuman reaction analysis receptor blocking structure activity relation trans isomer Adenine Deoxyadenosines Diphosphonates Erythrocytes Inositol Phosphates Phosphoric Acid Esters Receptors, Purinergic P2 Structure-Activity Relationship Turkey P2Y 1 receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The present study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gancyclovir, are generalizable to P2Y receptor ligands. Specifically, the binding site of the P2Y 1 receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and aromatic chains attached to the 9-position of adenine. Three groups of adenine derivatives having diverse side-chain structures, each containing two symmetrical phosphate or phosphonate groups, were prepared. Biological activity was demonstrated by the ability of the acyclic derivatives to act as agonists or antagonists in the stimulation of phospholipase C in turkey erythrocyte membranes. An acyclic N 6 -methyladenine derivative, 2-[2-(6- methylaminopurin-9-yl)-ethyl]-propane-1,3-bisoxy(diammoniumphosphate) (10), containing an isopentyl bisphosphate moiety, was a full antagonist at the P2Y 1 receptor with an IC 50 value of 1.60 μM. The corresponding 2-Cl derivative (11) was even more potent with an IC 50 value of 0.84 μM. Homologation of the ethylene group at the 9-position to 3-5 methylene units or inclusion of cis- or trans-olefinic groups greatly reduced antagonist potency at the P2Y 1 receptor. Analogues containing a diethanolamine amide group and an aryl di(methylphosphonate) were both less potent than 10 as antagonists, with IC 50 values of 14 and 16 μM, respectively, and no agonist activity was observed for these analogues. Thus, the ribose moiety is clearly not essential for recognition by the turkey P2Y 1 receptor, although a cyclic structure appears to be important for receptor activation, and the acyclic approach to the design of P2 receptor antagonists is valid. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222623_v43_n4_p746_Kim |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
2 [2 (2 chloro 6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) 2 [2 (6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) deoxyadenosine derivative ethylene derivative ganciclovir phospholipase C purine P2Y receptor purinergic receptor blocking agent receptor subtype unclassified drug animal cell article cis isomer controlled study drug potency drug receptor binding drug structure drug synthesis enzyme activation nonhuman reaction analysis receptor blocking structure activity relation trans isomer Adenine Deoxyadenosines Diphosphonates Erythrocytes Inositol Phosphates Phosphoric Acid Esters Receptors, Purinergic P2 Structure-Activity Relationship Turkey |
| spellingShingle |
2 [2 (2 chloro 6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) 2 [2 (6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) deoxyadenosine derivative ethylene derivative ganciclovir phospholipase C purine P2Y receptor purinergic receptor blocking agent receptor subtype unclassified drug animal cell article cis isomer controlled study drug potency drug receptor binding drug structure drug synthesis enzyme activation nonhuman reaction analysis receptor blocking structure activity relation trans isomer Adenine Deoxyadenosines Diphosphonates Erythrocytes Inositol Phosphates Phosphoric Acid Esters Receptors, Purinergic P2 Structure-Activity Relationship Turkey Kim, Y.-C. Gallo-Rodriguez, C. Jang, S.-Y. Nandanan, E. Adams, M. Harden, T.K. Boyer, J.L. Jacobson, K.A. Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists |
| topic_facet |
2 [2 (2 chloro 6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) 2 [2 (6 methylaminopurin 9 yl)ethyl]propane 1,3 bisoxy(diammoniumphosphate) deoxyadenosine derivative ethylene derivative ganciclovir phospholipase C purine P2Y receptor purinergic receptor blocking agent receptor subtype unclassified drug animal cell article cis isomer controlled study drug potency drug receptor binding drug structure drug synthesis enzyme activation nonhuman reaction analysis receptor blocking structure activity relation trans isomer Adenine Deoxyadenosines Diphosphonates Erythrocytes Inositol Phosphates Phosphoric Acid Esters Receptors, Purinergic P2 Structure-Activity Relationship Turkey |
| description |
P2Y 1 receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The present study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gancyclovir, are generalizable to P2Y receptor ligands. Specifically, the binding site of the P2Y 1 receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and aromatic chains attached to the 9-position of adenine. Three groups of adenine derivatives having diverse side-chain structures, each containing two symmetrical phosphate or phosphonate groups, were prepared. Biological activity was demonstrated by the ability of the acyclic derivatives to act as agonists or antagonists in the stimulation of phospholipase C in turkey erythrocyte membranes. An acyclic N 6 -methyladenine derivative, 2-[2-(6- methylaminopurin-9-yl)-ethyl]-propane-1,3-bisoxy(diammoniumphosphate) (10), containing an isopentyl bisphosphate moiety, was a full antagonist at the P2Y 1 receptor with an IC 50 value of 1.60 μM. The corresponding 2-Cl derivative (11) was even more potent with an IC 50 value of 0.84 μM. Homologation of the ethylene group at the 9-position to 3-5 methylene units or inclusion of cis- or trans-olefinic groups greatly reduced antagonist potency at the P2Y 1 receptor. Analogues containing a diethanolamine amide group and an aryl di(methylphosphonate) were both less potent than 10 as antagonists, with IC 50 values of 14 and 16 μM, respectively, and no agonist activity was observed for these analogues. Thus, the ribose moiety is clearly not essential for recognition by the turkey P2Y 1 receptor, although a cyclic structure appears to be important for receptor activation, and the acyclic approach to the design of P2 receptor antagonists is valid. |
| format |
JOUR |
| author |
Kim, Y.-C. Gallo-Rodriguez, C. Jang, S.-Y. Nandanan, E. Adams, M. Harden, T.K. Boyer, J.L. Jacobson, K.A. |
| author_facet |
Kim, Y.-C. Gallo-Rodriguez, C. Jang, S.-Y. Nandanan, E. Adams, M. Harden, T.K. Boyer, J.L. Jacobson, K.A. |
| author_sort |
Kim, Y.-C. |
| title |
Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists |
| title_short |
Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists |
| title_full |
Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists |
| title_fullStr |
Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists |
| title_full_unstemmed |
Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y 1 receptor antagonists |
| title_sort |
acyclic analogues of deoxyadenosine 3',5'-bisphosphates as p2y 1 receptor antagonists |
| url |
http://hdl.handle.net/20.500.12110/paper_00222623_v43_n4_p746_Kim |
| work_keys_str_mv |
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| _version_ |
1782028852833288192 |