- Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias
-
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.
- Kennedy, Nicole M.,Schmid, Cullen L.,Ross, Nicolette C.,Lovell, Kimberly M.,Yue, Zhizhou,Chen, Yen Ting,Cameron, Michael D.,Bohn, Laura M.,Bannister, Thomas D.
-
p. 8895 - 8907
(2018/10/05)
-
- Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives
-
STATs are transcription factors acting as intracellular signaling after stimulation with cytokines, growth factors and hormones. STAT5 is also constitutively active in many forms of cancers, including chronic myelogenous leukemia, acute lymphoblastic leukemia and Hodgkin's lymphoma. Recently, literature reported that the neuroleptic drug pimozide inhibits STAT5 phosphorylation inducing apoptosis in CML cells. We undertook an investigation from pimozide structure, obtaining simple derivatives with cytotoxic and STAT5-inhibitory activity, two of them markedly more potent than pimozide.
- Rondanin, Riccardo,Simoni, Daniele,Romagnoli, Romeo,Baruchello, Riccardo,Marchetti, Paolo,Costantini, Cristiana,Fochi, Sara,Padroni, Giacomo,Grimaudo, Stefania,Pipitone, Rosaria Maria,Meli, Maria,Tolomeo, Manlio
-
supporting information
p. 4568 - 4574
(2015/02/19)
-
- 2-benzimidazolylamine compounds as ORL-1-receptor agonists
-
A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently selected from hydrogen, halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl and the like; R3and R4are independently selected from hydrogen, halo(C1-C10)alkyl, optionally substituted (C1-C6)alkyl and the like, or R3and R4, together with the nitrogen atom to which they are attached, form an optionally substituted fully saturated, partially saturated or fully unsaturated heterocyclic ring; and R5is (C4-C11)cycloalkyl and the like, has ORL1-receptor agonist activity, and are useful as analgesics or the like in mammalian subjects.
- -
-
Page column 21
(2008/06/13)
-
- 2-oxoimidazole derivatives
-
The present invention relates to a compound represented by Formula [I] wherein represents an aromatic carbo- or heterocyclic ring which may have a substituent; Cy represents a mono-, bi- or tricyclic aliphatic carbocyclic group having 3 to 20 carbon atoms, which may have a substituent; represents a mono- or bicyclic aliphatic nitrogen-containing heterocyclic group having 3 to 14 carbon atoms, which may have a substituent; R1represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a cyclo(lower alkyl) group, an amino group, a lower alkylamino group, a di(lower alkyl)-amino group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di(lower alkyl)carbamoyl group, or a lower alkyl group which may have a substituent; and R2represents a hydrogen atom or a lower alkyl group, a salt or ester thereof, a production process for the same, and an analgesic, a reliever against tolerance to a narcotic analgesic represented by morphine, a reliever against dependence on a narcotic analgesic represented by morphine, an analgesic enhancer, an antiobestic, a drug for ameliorating brain function, a remedy for schizophrenia, a remedy for Parkinsonism, a remedy for chorea, an antidepressant, a remedy for diabetes insipidus, a remedy for polyuria, or a remedy for hypotension, comprising an effective ingredient of the same.
- -
-
-