Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics
The adenosine A1 receptor (A<sub>1</sub>R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to over...
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MDPI AG
2024-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/24/2121 |
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| author | Tal Weizmann Abigail Pearce Peter Griffin Achille Schild Maren Flaßhoff Philipp Grossenbacher Martin Lochner Christopher A. Reynolds Graham Ladds Giuseppe Deganutti |
| author_facet | Tal Weizmann Abigail Pearce Peter Griffin Achille Schild Maren Flaßhoff Philipp Grossenbacher Martin Lochner Christopher A. Reynolds Graham Ladds Giuseppe Deganutti |
| author_sort | Tal Weizmann |
| collection | DOAJ |
| description | The adenosine A1 receptor (A<sub>1</sub>R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the positive allosteric modulator MIPS521 and the A1R-selective agonist BnOCPA, which are both potent and powerful analgesics with fewer side effects. While BnOCPA directly activates the A<sub>1</sub>R from the canonical orthosteric site, MIPS521 binds to an allosteric site, acting in concert with orthosteric adenosine and tuning its pharmacology. Given their overlapping profile in pain models but distinct mechanisms of action, we combined pharmacology and microsecond molecular dynamics simulations to address MIPS521 and BnOCPA activity and their reciprocal influence when bound to the A1R. We show that MIPS521 changes adenosine and BnOCPA G protein selectivity in opposite ways and propose a structural model where TM7 dynamics are differently affected and involved in the G protein preferences of adenosine and BnOCPA. |
| format | Article |
| id | doaj-art-f4b2272fbbb04102bcc335b3deb5398b |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-f4b2272fbbb04102bcc335b3deb5398b2024-12-27T14:16:39ZengMDPI AGCells2073-44092024-12-011324212110.3390/cells13242121Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid AnalgesicsTal Weizmann0Abigail Pearce1Peter Griffin2Achille Schild3Maren Flaßhoff4Philipp Grossenbacher5Martin Lochner6Christopher A. Reynolds7Graham Ladds8Giuseppe Deganutti9Centre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UKDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKCentre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UKInstitute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, SwitzerlandCentre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UKDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKCentre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UKThe adenosine A1 receptor (A<sub>1</sub>R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the positive allosteric modulator MIPS521 and the A1R-selective agonist BnOCPA, which are both potent and powerful analgesics with fewer side effects. While BnOCPA directly activates the A<sub>1</sub>R from the canonical orthosteric site, MIPS521 binds to an allosteric site, acting in concert with orthosteric adenosine and tuning its pharmacology. Given their overlapping profile in pain models but distinct mechanisms of action, we combined pharmacology and microsecond molecular dynamics simulations to address MIPS521 and BnOCPA activity and their reciprocal influence when bound to the A1R. We show that MIPS521 changes adenosine and BnOCPA G protein selectivity in opposite ways and propose a structural model where TM7 dynamics are differently affected and involved in the G protein preferences of adenosine and BnOCPA.https://www.mdpi.com/2073-4409/13/24/2121adenosine A1 receptorBnOCPAMIPS521non-opioid analgesiaGPCRs |
| spellingShingle | Tal Weizmann Abigail Pearce Peter Griffin Achille Schild Maren Flaßhoff Philipp Grossenbacher Martin Lochner Christopher A. Reynolds Graham Ladds Giuseppe Deganutti Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics Cells adenosine A1 receptor BnOCPA MIPS521 non-opioid analgesia GPCRs |
| title | Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics |
| title_full | Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics |
| title_fullStr | Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics |
| title_full_unstemmed | Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics |
| title_short | Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics |
| title_sort | mechanistic insights into the adenosine a1 receptor s positive allosteric modulation for non opioid analgesics |
| topic | adenosine A1 receptor BnOCPA MIPS521 non-opioid analgesia GPCRs |
| url | https://www.mdpi.com/2073-4409/13/24/2121 |
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