Positive allosteric mechanisms of adenosine A₁ receptor-mediated analgesia.

ABSTRACT: The adenosine A₁ receptor (A₁R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain^1,2. However, development of analgesic orthosteric A₁R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects³. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A₁R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A₁R co-bound to adenosine, MIPS521 and a G_i2 heterotrim

SUBMITTER: Draper-Joyce CJ 

PROVIDER: S-EPMC8711093 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature