The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives
A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A2B adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA2B AR but they displayed affinity at the hA3 AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA3 AR Ki = 11 nM) and selectivity (A1/A3 and A2A/A3 > 9090; A2B/A3 > 909) at the hA3 AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2015 |
|---|---|
| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
PloS one - 10(2015), 12 vom: 24., Seite e0143504 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Federico, Stephanie [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
3QD5KJZ7ZJ |
|---|
| Anmerkungen: |
Date Completed 23.06.2016 Date Revised 13.11.2018 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pone.0143504 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM25517540X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM25517540X | ||
| 003 | DE-627 | ||
| 005 | 20231224173940.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2015 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pone.0143504 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0850.xml |
| 035 | |a (DE-627)NLM25517540X | ||
| 035 | |a (NLM)26625265 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Federico, Stephanie |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives |
| 264 | 1 | |c 2015 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.06.2016 | ||
| 500 | |a Date Revised 13.11.2018 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A2B adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA2B AR but they displayed affinity at the hA3 AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA3 AR Ki = 11 nM) and selectivity (A1/A3 and A2A/A3 > 9090; A2B/A3 > 909) at the hA3 AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Purinergic P1 Receptor Antagonists |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a Receptors, Purinergic P1 |2 NLM | |
| 650 | 7 | |a pyrazole |2 NLM | |
| 650 | 7 | |a 3QD5KJZ7ZJ |2 NLM | |
| 650 | 7 | |a pyrimidine |2 NLM | |
| 650 | 7 | |a K8CXK5Q32L |2 NLM | |
| 700 | 1 | |a Redenti, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Sturlese, Mattia |e verfasserin |4 aut | |
| 700 | 1 | |a Ciancetta, Antonella |e verfasserin |4 aut | |
| 700 | 1 | |a Kachler, Sonja |e verfasserin |4 aut | |
| 700 | 1 | |a Klotz, Karl-Norbert |e verfasserin |4 aut | |
| 700 | 1 | |a Cacciari, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Moro, Stefano |e verfasserin |4 aut | |
| 700 | 1 | |a Spalluto, Giampiero |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 10(2015), 12 vom: 24., Seite e0143504 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2015 |g number:12 |g day:24 |g pages:e0143504 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0143504 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2015 |e 12 |b 24 |h e0143504 | ||