{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T23:11:47Z","timestamp":1773702707349,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T00:00:00Z","timestamp":1734739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"BBSCR","doi-asserted-by":"publisher","award":["BB\/W016974\/1"],"award-info":[{"award-number":["BB\/W016974\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"BBSCR","doi-asserted-by":"publisher","award":["BB\/W014831\/1"],"award-info":[{"award-number":["BB\/W014831\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"BBSCR","doi-asserted-by":"publisher","award":["INF\/R2\/212001"],"award-info":[{"award-number":["INF\/R2\/212001"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Royal Society Industry Fellowship","award":["BB\/W016974\/1"],"award-info":[{"award-number":["BB\/W016974\/1"]}]},{"name":"Royal Society Industry Fellowship","award":["BB\/W014831\/1"],"award-info":[{"award-number":["BB\/W014831\/1"]}]},{"name":"Royal Society Industry Fellowship","award":["INF\/R2\/212001"],"award-info":[{"award-number":["INF\/R2\/212001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The adenosine A1 receptor (A1R) 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 A1R 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.<\/jats:p>","DOI":"10.3390\/cells13242121","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T05:58:27Z","timestamp":1734933507000},"page":"2121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanistic Insights into the Adenosine A1 Receptor\u2019s Positive Allosteric Modulation for Non-Opioid Analgesics"],"prefix":"10.3390","volume":"13","author":[{"given":"Tal","family":"Weizmann","sequence":"first","affiliation":[{"name":"Centre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail","family":"Pearce","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Griffin","sequence":"additional","affiliation":[{"name":"Centre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7987-8013","authenticated-orcid":false,"given":"Achille","family":"Schild","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maren","family":"Fla\u00dfhoff","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-6882","authenticated-orcid":false,"given":"Philipp","family":"Grossenbacher","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4930-1886","authenticated-orcid":false,"given":"Martin","family":"Lochner","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9267-5141","authenticated-orcid":false,"given":"Christopher A.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Centre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7320-9612","authenticated-orcid":false,"given":"Graham","family":"Ladds","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-2986","authenticated-orcid":false,"given":"Giuseppe","family":"Deganutti","sequence":"additional","affiliation":[{"name":"Centre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0301-0082(03)00050-9","article-title":"Adenosine in the spinal cord and periphery: Release and regulation of pain","volume":"69","author":"Sawynok","year":"2003","journal-title":"Prog. 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