ELISSA A. FINK HTTPS://ORCID.ORG/0000-0001-5531-1971JUN XU HTTPS://ORCID.ORG/0000-0002-1600-583XHARALD HÜBNER HTTPS://ORCID.ORG/0000-0002-7892-599XJOAO M. BRAZ HTTPS://ORCID.ORG/0000-0001-8955-0735PHILIPP SEEMANN HTTPS://ORCID.ORG/0000-0002-7575-2181CHARLOTTE AVETVERONICA CRAIK HTTPS://ORCID.ORG/0000-0001-5463-1199DOROTHEE WEIKERT HTTPS://ORCID.ORG/0000-0003-2259-9002MAXIMILIAN F. SCHMIDT HTTPS://ORCID.ORG/0000-0002-7055-2439PETER GMEINER HTTPS://ORCID.ORG/0000-0002-4127-197X
A path to pain relief
The serious problems associated with opioid addiction have motivated the search for non-opioid pain-relief drugs. The α2A-adrenergic receptor (α2AAR) is a validated pain receptor and is targeted by dexmetadomine, a drug used in hospitals but unsuitable for broader use because it causes sedation and is not orally bioavailable. Fink et al. screened more than 300 million virtual molecules and identified agonists that bind α2AAR with reasonable affinity and are structurally unrelated to known agonists. Experimental structures of two of the compounds bound to α2AAR allowed optimization to improve potency. The optimized compounds were effective in a neuropathic pain model without causing sedation, making them promising leads for further development. —VV
Structured Abstract
INTRODUCTION
Epidemics of pain and opioid abuse underscore the need for new nonopioid therapeutics to treat pain. Many nonopioid receptors are involved in pain processing (nociception), but only a few have been validated therapeutically. Of particular interest is the α2A-adrenergic receptor (α2AAR), a G protein–coupled receptor (GPCR) whose activation in the central nervous system has pain-relieving effects. The known therapeutics targeting the α2AAR, like clonidine and dexmedetomidine, are known to be analgesic. They are also strongly sedating, which is important for the primary indication of dexmedetomidine. This, however, has restricted the use of these drugs to hospital settings and kept them from being used in broader patient populations.
RATIONALE
Because GPCRs, like α2AAR, can signal into the cell through multiple downstream effectors, we reasoned that agonists that were chemically dissimilar to the highly related dexmedetomidine, clonidine, and brimonidine might have different signaling and might be able to separate sedation from analgesia. We sought these chemotypes among a virtual library of more than 301 million diverse, readily accessible molecules in the ZINC15 library (http://zinc15.docking.org), few of which have been previously synthesized. We computationally docked each virtual molecule into the highly similar α2BAR binding site, prioritizing those that physically fit and that were chemically unrelated to the known drugs.
RESULTS
From the high-ranking docked compounds, we selected 48 for de novo synthesis and testing. Against the α2BAR used in the virtual docking screens, 30 molecules bound for a 63% hit rate, among the highest to date for docking campaigns. Seventeen further bound to α2AAR with binding constants in the low-nanomolar to low-micromolar concentration range. Several acted as full or partial agonists of α2AAR, activating the receptor. Among these was ‘9087 [mean effective concentration (EC50) of 52 nM]. Notably, the docking-derived agonists preferentially activated Gi, Go, and Gz G protein subtypes, which contrasts with known drugs, like dexmedetomidine and brimonidine, that activate a much broader set of G proteins and recruit β-arrestins. Thus, the new agonists activate a more selective set of cellular pathways than the known α2AAR drugs, something we had hoped for when prioritizing new chemotypes.
The structures of two of these agonists were experimentally determined in complex with the activated state of α2AAR. These experimental ligand geometries closely corresponded to computational predictions. They also templated the optimization of the initial docking hits and led to more potent analogs, including PS75 (EC50 4.8 nM). The physical features of these agonists allowed them to reach high brain concentrations after systemic dosing. In animal behavioral assays, six of these previously uncharacterized agonists relieved pain behaviors in neuropathic, inflammatory, and acute thermal nociception assays. Gene mutation and reversal of receptor binding with an α2AR antagonist confirmed that analgesia occurred primarily through α2AAR. Crucially, when compared with dexmedetomidine, none of the new compounds caused sedation, even at substantially higher doses than required for pain relief.
CONCLUSION
The separation of analgesic properties from sedation of the new agonists is important for further α2AAR drug development. The newly identified agonists, especially ‘9087 and PS75, overcome the sedation liability of the previously known drugs, and several are orally bioavailable. This makes them lead molecules for the development of nonopioid pain therapeutics.
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