Mechanistic Insights into the Adenosine A1 Receptor's Positive Allosteric Modulation for Non-Opioid Analgesics.

ABSTRACT: 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 dyna

SUBMITTER: Weizmann T 

PROVIDER: S-EPMC11726717 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature