Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist

Brotherton‐Pleiss, Christine; Dillon, Michael P.; Ford, Anthony; Gever, Joel R.; Carter, David S.; Gleason, Shelley; Lin, Clara J.; Moore, Amy G.; Thompson, Anthony W.; Villa, M.; Zhai, Yansheng

doi:10.1016/j.bmcl.2009.12.044

Cited by 40 publications

(28 citation statements)

References 11 publications

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“…RO-5 also inhibits native presynaptic P2X3Rs and P2X2/3Rs (Kaan et al, 2010). 1-Methyl-3-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid [(R)-2-(4-acetylpiperazin-1-yl)-1-methyl-ethyl]-amide (RO-85) has demonstrated selectivity for P2X3Rs (IC 50 ϭ 30 nM) over heteromeric P2X2/3Rs (IC 50 ϭ 400 nM) and other P2XRs (IC 50 Ͼ 10 M), indicating the pharmacological possibility to distinguish between homomeric and heteromeric P2X3Rs (Brotherton-Pleiss et al, 2010). Finally, AF-353 inhibits hP2X3R (IC 50 , 10 nM), rP2X3R (IC 50 , 10 nM), and hP2X2/3R (IC 50 , 38 nM) at low nanomolar concentrations .…”

Section: Activation and Regulation Of P2xrsmentioning

confidence: 99%

Activation and Regulation of Purinergic P2X Receptor Channels

et al. 2011

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Section: Activation and Regulation Of P2xrsmentioning

confidence: 99%

Activation and Regulation of Purinergic P2X Receptor Channels

et al. 2011

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“…Furthermore, it was able to attenuate bone cancer pain behavior in rats [145]. RO-85, an orally bioavailable drug-like P2X3 receptor antagonist, is selective for the P2X3 receptor over the P2X2/3 and other P2X receptor subtypes [146]. Three additional P2X3 and P2X2/3 selective diaminopyrimidine derivatives (compounds A, B, and C) with nanomolar potency were recently published by GlaxoSmithKline [147].…”

Section: Pharmacological Characteristics Of P2x Receptorsmentioning

confidence: 99%

Molecular and functional properties of P2X receptors—recent progress and persisting challenges

Kaczmarek-Hájek

Lörinczi

Hausmann

et al. 2012

Purinergic Signalling

197

202

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ATP-gated P2X receptors are trimeric ion channels that assemble as homo- or heteromers from seven cloned subunits. Transcripts and/or proteins of P2X subunits have been found in most, if not all, mammalian tissues and are being discovered in an increasing number of non-vertebrates. Both the first crystal structure of a P2X receptor and the generation of knockout (KO) mice for five of the seven cloned subtypes greatly advanced our understanding of their molecular and physiological function and their validation as drug targets. This review summarizes the current understanding of the structure and function of P2X receptors and gives an update on recent developments in the search for P2X subtype-selective ligands. It also provides an overview about the current knowledge of the regulation and modulation of P2X receptors on the cellular level and finally on their physiological roles as inferred from studies on KO mice.

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“…Likewise, Ip 5 I was shown to inhibit α,βme-ATP-induced responses of homomeric P2X1 and P2X3 receptors with low micromolar potency, but is virtually inactive at the heteromeric P2X2/3R and the homomeric P2X2R (King et al, 1999; Dunn et al, 2000). Also RO-85, an orally bioavailable drug-like P2X3R antagonist, is selective for the P2X3R over the P2X2/3R and other P2XR subtypes (Brotherton-Pleiss et al, 2010). Interestingly, all these substances appear to lose their affinity at the heteromeric receptor despite the fact that at least one P2X3-P2X3 interface is preserved in the heteromer.…”

Section: Properties Of Heterologously Expressed P2xrsmentioning

confidence: 99%

Heteromeric assembly of P2X subunits

Saul

Hausmann

Kless³

et al. 2013

Front. Cell. Neurosci.

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Transcripts and/or proteins of P2X receptor (P2XR) subunits have been found in virtually all mammalian tissues. Generally more than one of the seven known P2X subunits have been identified in a given cell type. Six of the seven cloned P2X subunits can efficiently form functional homotrimeric ion channels in recombinant expression systems. This is in contrast to other ligand-gated ion channel families, such as the Cys-loop or glutamate receptors, where homomeric assemblies seem to represent the exception rather than the rule. P2XR mediated responses recorded from native tissues rarely match exactly the biophysical and pharmacological properties of heterologously expressed homomeric P2XRs. Heterotrimerization of P2X subunits is likely to account for this observed diversity. While the existence of heterotrimeric P2X2/3Rs and their role in physiological processes is well established, the composition of most other P2XR heteromers and/or the interplay between distinct trimeric receptor complexes in native tissues is not clear. After a description of P2XR assembly and the structure of the intersubunit ATP-binding site, this review summarizes the distribution of P2XR subunits in selected mammalian cell types and the biochemically and/or functionally characterized heteromeric P2XRs that have been observed upon heterologous co-expression of P2XR subunits. We further provide examples where the postulated heteromeric P2XRs have been suggested to occur in native tissues and an overview of the currently available pharmacological tools that have been used to discriminate between homo- and heteromeric P2XRs.

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Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist

Cited by 40 publications

References 11 publications

Activation and Regulation of Purinergic P2X Receptor Channels

Activation and Regulation of Purinergic P2X Receptor Channels

Molecular and functional properties of P2X receptors—recent progress and persisting challenges

Heteromeric assembly of P2X subunits

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