Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 19, Pages 8895-8907Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01136
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Funding
- NIH [R01DA033073, R01DA038694]
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA033073] Funding Source: NIH RePORTER
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While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal beta arrestin-mediated signaling because MOR agonist-treated beta arrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/beta arr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.
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