Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias.

Autor:	Kennedy NM; Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Schmid CL; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Ross NC; Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Lovell KM; Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Yue Z; Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Chen YT; Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Cameron MD; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Bohn LM; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States., Bannister TD; Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.; Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Oct 11; Vol. 61 (19), pp. 8895-8907. Date of Electronic Publication: 2018 Sep 24.
DOI:	10.1021/acs.jmedchem.8b01136
Abstrakt:	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 βarrestin-mediated signaling because MOR agonist-treated βarrestin2 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/βarr2). 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.
Databáze:	MEDLINE
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