Author: Ayhan, Mehmet Menaf ; Cheng, Gang ; Kalyanaraman, Balaraman ; Hardy, Micael ; Sikora, Adam ; Ouari, Olivier ; Lambeth, J David ; Zielonka, Jacek ; VerPlank, Lynn ; Podsiadły, Radosław ; Zielonka, Monika

Using high throughput screening-compatible assays for superoxide and hydrogen peroxide, we identified potential inhibitors of the NADPH oxidase (Nox2) isoform from a small library of bioactive compounds. By using multiple probes (hydroethidine, hydropropidine, Amplex Red, and coumarin boronate) with well defined redox chemistry that form highly diagnostic marker products upon reaction with superoxide (O2 (̇̄)), hydrogen peroxide (H2O2), and peroxynitrite (ONOO(-)), the number of false positives was greatly decreased. Selected hits for Nox2 were further screened for their ability to inhibit ONOO(-)formation in activated macrophages. A new diagnostic marker product for ONOO(-)is reported. We conclude that the newly developed high throughput screening/reactive oxygen species assays could also be used to identify potential inhibitors of ONOO(-)formed from Nox2-derived O2 (̇̄)and nitric oxide synthase-derived nitric oxide.

01 Oct 2014·European Journal of PharmacologyQ3 · MEDICINE

Identification of novel small molecule modulators of K2P18.1 two-pore potassium channel

Q3 · MEDICINE

Article

Author: Zhang, Yixin ; Schmidt, Katharina ; Bruner, J Kyle ; Li, Min ; Zou, Beiyan ; Zhang, Hongkang

Two-pore domain potassium (K2P) channels are responsible for background potassium (K+) current, which is crucial for the maintenance of resting membrane potential. K2P18.1, also called TWIK-related spinal cord K+ channel (TRESK) or KCNK18, is thought to be a major contributor to background K+ currents, particularly in sensory neurons where it is abundantly expressed. Despite its critical role and potential therapeutic implication, pharmacological tools for probing K2P18.1 activity remain unavailable. Here, we report a high-throughput screen against a collection of bioactive compounds that yielded 26 inhibitors and 8 activators of K2P18.1 channel activity with more than 10-fold selectivity over the homologous channel K2P9.1. Among these modulators, the antihistamine loratadine inhibited K2P18.1 activity with IC50 of 0.49±0.23 µM and is considerably more potent than existing K2P18.1 inhibitors. Importantly, the inhibition by loratadine remains equally efficacious upon potentiation of K2P18.1 by calcium signaling. Furthermore, the loratadine effect is dependent on transmembrane residues F145 and F352, providing orthogonal evidence that the inhibition is caused by a direct compound-channel interaction. This study reveals new pharmacological modulators of K2P18.1 activity useful in dissecting native K2P18.1 function.

01 Feb 2014·British Journal of Pharmacology

Novel vasocontractile role of the P2Y₁₄ receptor: characterization of its signalling in porcine isolated pancreatic arteries

Article

Author: Chan, S L F ; Ralevic, V ; Latif, M L ; Alsaqati, M

Background and PurposeThe P2Y14 receptor is the newest member of the P2Y receptor family; it is Gi/o protein‐coupled and is activated by UDP and selectively by UDP‐glucose and MRS2690 (2‐thiouridine‐5′‐diphosphoglucose) (7–10‐fold more potent than UDP‐glucose). This study investigated whether P2Y14 receptors were functionally expressed in porcine isolated pancreatic arteries.Experimental ApproachPancreatic arteries were prepared for isometric tension recording and UDP‐glucose, UDP and MRS2690 were applied cumulatively after preconstriction with U46619, a TxA2 mimetic. Levels of phosphorylated myosin light chain 2 (MLC2) were assessed with Western blotting. cAMP concentrations were assessed using a competitive enzyme immunoassay kit.Key ResultsConcentration‐dependent contractions with a rank order of potency of MRS2690 (10‐fold) > UDP‐glucose ≥ UDP were recorded. These contractions were reduced by PPTN {4‐[4‐(piperidin‐4‐yl)phenyl]‐7‐[4‐(trifluoromethyl)phenyl]‐2‐naphthoic acid}, a selective antagonist of P2Y14 receptors, which did not affect responses to UTP. Contraction to UDP‐glucose was not affected by MRS2578, a P2Y6 receptor selective antagonist. Raising cAMP levels and forskolin, in the presence of U46619, enhanced contractions to UDP‐glucose. In addition, UDP‐glucose and MRS2690 inhibited forskolin‐stimulated cAMP levels. Removal of the endothelium and inhibition of endothelium‐derived contractile agents (TxA2, PGF2α and endothelin‐1) inhibited contractions to UDP glucose. Y‐27632, nifedipine and thapsigargin also reduced contractions to the agonists. UDP‐glucose and MRS2690 increased MLC2 phosphorylation, which was blocked by PPTN.Conclusions and ImplicationsP2Y14 receptors play a novel vasocontractile role in porcine pancreatic arteries, mediating contraction via cAMP‐dependent mechanisms, elevation of intracellular Ca2+ levels, activation of RhoA/ROCK signalling and MLC2, along with release of TxA2, PGF2α and endothelin‐1.

100 Deals associated with L-655240

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	Phase 1	-	Merck Sharp & Dohme Corp.	-
Arrhythmias, Cardiac	Phase 1	Canada	Merck Frosst Co.	-
Asthma	Phase 1	-	Merck Sharp & Dohme Corp.	-
Asthma	Phase 1	Canada	Merck Frosst Co.	-
Myocardial Ischemia	Phase 1	-	Merck Sharp & Dohme Corp.	-
Myocardial Ischemia	Phase 1	Canada	Merck Frosst Co.	-

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