Drug-like antagonists of P2Y receptors — from lead identification to drug development

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation

Drug-like antagonists of P2Y receptors — from lead identification to drug development

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation

Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925

The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. As such, there is a need for new hP2Y2R antagonists and molecular probes to study this receptor. Herein, we report the development of a new series of non-nucleotide hP2Y2R antagonists leading to the discovery of a series of fluorescent ligands containing different linkers and fluorophores based on the known, non-nucleotide hP2Y2R antagonist AR-C118925 (1). One of these conjugates 98 displayed micromolar affinity for the hP2Y2R (pKd = 6.32 ± 0.10; n=17) using a bioluminescence energy transfer (BRET) assay. Confocal microscopy with this ligand revealed displaceable membrane labeling of astrocytoma cells expressing un-tagged hP2Y2R. These properties, make 98 one of the first tools for studying hP2Y2R distribution and organization

The global build-up to intrinsic edge localized mode bursts seen in divertor full flux loops in JET

A global signature of the build-up to an intrinsic edge localized mode (ELM) is found in the temporal analytic phase of signals measured in full flux azimuthal loops in the divertor region of JET. Toroidally integrating, full flux loop signals provide a global measurement proportional to the voltage induced by changes in poloidal magnetic flux; they are electromagnetically induced by the dynamics of spatially integrated current density. We perform direct time-domain analysis of the high time-resolution full flux loop signals VLD2 and VLD3. We analyze plasmas where a steady H-mode is sustained over several seconds during which all the observed ELMs are intrinsic; there is no deliberate intent to pace the ELMing process by external means. ELM occurrence times are determined from the Be II emission at the divertor. We previously [Chapman et al., Phys. Plasmas 21, 062302 (2014); Chapman et al., in 41st EPS Conference on Plasma Physics, Europhysics Conference Abstracts (European Physical Society, 2014), Vol. 38F, ISBN 2-914771-90-8] found that the occurrence times of intrinsic ELMs correlate with specific temporal analytic phases of the VLD2 and VLD3 signals. Here, we investigate how the VLD2 and VLD3 temporal analytic phases vary with time in advance of the ELM occurrence time. We identify a build-up to the ELM in which the VLD2 and VLD3 signals progressively align to the temporal analytic phase at which ELMs preferentially occur, on a ∼2−5ms timescale. At the same time, the VLD2 and VLD3 signals become temporally phase synchronized with each other, consistent with the emergence of coherent global dynamics in the integrated current density. In a plasma that remains close to a global magnetic equilibrium, this can reflect bulk displacement or motion of the plasma. This build-up signature to an intrinsic ELM can be extracted from a time interval of data that does not extend beyond the ELM occurrence time, so that these full flux loop signals could assist in ELM prediction or mitigation

The variance shared across forms of childhood trauma is strongly associated with liability for psychiatric and substance use disorders

Introduction: Forms of childhood trauma tend to co-occur and are associated with increased risk for psychiatric and substance use disorders. Commonly used binary measures of trauma exposure have substantial limitations. Methods: We performed multigroup confirmatory factor analysis (CFA), separately by sex, using data from the Childhood Trauma (CT) Study's sample of twins and siblings (N = 2594) to derive three first-order factors (childhood physical abuse, childhood sexual abuse, and parental partner abuse) and, as hypothesized, one higher order, childhood trauma factor (CTF) representing a measure of their common variance. Results: CFA produced a good-fitting model in the CT Study; we replicated the model in the Comorbidity and Trauma (CAT) Study's sample (N = 1981) of opioid-dependent cases and controls. In both samples, first-order factors are moderately correlated (indicating they measure largely unique, but related constructs) and their loadings on the CTF suggest it provides a reasonable measure of their common variance. We examined the association of CTF score with risk for psychiatric and substance use disorders in these samples and the OZ-ALC GWAS sample (N = 1538) in which CT Study factor loadings were applied. We found that CTF scores are strongly associated with liability for psychiatric and substance use disorders in all three samples; estimates of risk are extremely consistent across samples. Conclusions: The CTF is a continuous, robust measure that captures the common variance across forms of childhood trauma and provides a means to estimate shared liability while avoiding multicollinearity. Confirmatory factor analysis was used to derive a higher order, childhood trauma factor representing a measure of the common variance across three forms of trauma: childhood physical abuse, childhood sexual abuse, and parental partner abuse. We replicated the model in a second sample. We then examined the association of childhood trauma score with risk for psychiatric and substance use disorders in these samples and a third sample in which the primary sample's factor loadings were applied finding factor scores to be strongly and consistently associated with liability for psychiatric and substance use disorders in all three samples