Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

Exogenous Integrin αIIbβ3 Inhibitors Revisited: Past,Present and Future Applications

The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express anticoagulant and antiplatelet proteins, which represent major sources of lead compounds for the development of useful therapeutic agents for the treatment of haemostatic disorders or cardiovascular diseases. In addition to hematophagous parasites, snakes also possess anticoagulant and antiplatelet proteins in their salivary glands. Two snake venom proteins have been developed into two antiplatelet drugs that are currently used in the clinic. The group of proteins discussed in this review are disintegrins, low molecular weight integrin-binding cysteine-rich proteins, found in snakes, ticks, leeches, worms and horseflies. Finally, we highlight various oral antagonists, which have been tested in clinical trials but were discontinued due to an increase in mortality. No new αIIbβ3 inhibitors are developed since the approval of current platelet antagonists, and structure-function analysis of exogenous disintegrins could help find platelet antagonists with fewer adverse side effects.     

m-Chlorophenylpiperazine (mCPP) Modulates the Discriminative Stimulus Effects of Cocaine Through Actions at the 5-HT?C Receptor.

Agonists acting at the serotonin-1B receptor (5-HT?BR) and 5-HT?CR have been reported to potentiate and block, respectively, the discriminative stimulus effects of cocaine. The present investigation reassessed the antagonistic effects of the mixed 5-HT?C/?BR agonist m-chlorophenylpiperazine (mCPP) on the discriminative stimulus effects of cocaine in the presence or absence of selective antagonism of the 5-HT?BR or 5-HT?CR. The stimulus effects of cocaine were attenuated by mCPP at doses that reduced response rates. The selective 5-HT?CR antagonist SB 242084, but not the selective 5-HT?BR antagonist GR 127935, reversed the mCPP-evoked attenuation of the cocaine cue and the suppression of response rates. These results demonstrate that the suppressive effects of mCPP on cocaine discrimination are related to stimulation of the HT?CR. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides

The insulin receptor (IR) is a transmembrane protein that is activated by ligands in insulin signaling pathways. The IR has been considered as a novel therapeutic target for clinical intervention, considering the overexpression of its protein and A-isoform in multiple cancers, Alzheimer’s disease, and Type 2 diabetes mellitus in humans. Meanwhile, it may also serve as a potential target in pest management due to its multiple physiological influences in insects. In this review, we provide an overview of the structural and molecular biology of the IR, functions of IRs in humans and insects, physiological and nonpeptide small molecule modulators of the IR, and the regulating mechanisms of the IR. Xenobiotic compounds and the corresponding insecticidal chemicals functioning on the IR are also discussed. This review is expected to provide useful information for a better understanding of human IR-related diseases, as well as to facilitate the development of novel small-molecule activators and inhibitors of the IR for use as medicines or pesticides.     

[2.2]Paracyclophane-Based TCN-201 Analogs as GluN2A-Selective NMDA Receptor Antagonists

Recent studies have shown the involvement of GluN2A subunit-containing NMDA receptors in various neurological and pathological disorders. In the X-ray crystal structure, TCN-201 ( 1 ) and analogous pyrazine derivatives 2 and 3 adopt a U-shape (hairpin) conformation within the binding site formed by the ligand binding domains of the GluN1 and GluN2A subunits. In order to mimic the resulting π/π-interactions of two aromatic rings in the binding site, a [2.2]paracyclophane system was designed to lock these aromatic rings in a parallel orientation. Acylation of [2.2]paracyclophane ( 5 ) with oxalyl chloride and chloroacetyl chloride and subsequent transformations led to the oxalamide 7 , triazole 10 and benzamides 12 . The GluN2A inhibitory activities of the paracyclophane derivatives were tested with two-electrode voltage clamp electrophysiology using Xenopus laevis oocytes expressing selectively functional NMDA receptors with GluN2A subunit. The o-iodobenzamide 12 b with the highest similarity to TCN-201 showed the highest GuN2A inhibitory activity of this series of compounds. At a concentration of 10 μM, 12 b reached 36 % of the inhibitory activity of TCN-201 ( 1 ). This result indicates that the [2.2]paracyclophane system is well accepted by the TCN-201 binding site.     

A multifaceted approach to harness probiotics as antagonists on plant based foods,for enhanced benefits to be reaped at a global level

Investigations into probiotics have focused on their health benefits thus far, with some of the findings finally reaching the food and pharmaceutical industries, which have used them for commercial purposes. In biocontrol research some microbes, mainly isolated from plants, have shown antagonism towards both enteric and plant pathogens, and some of them represent probiotic species. Fresh fruits and vegetables are regarded as health‐promoting dietary constituents, and if probiotics could be used to control the pathogens on them then they could turn out to be even healthier. The fresh produce industry still depends on agrochemicals and the increase in the demand for high‐priced organically grown produce indicates consumer concerns regarding the use of agrochemicals. If the potential of probiotic organisms to serve as biocontrol agents for fresh produce is exploited, all fresh produce can be made as safe as organically grown produce, and much more wholesome. This review appraises the feasibility of such a move by evaluating how research has progressed in both disciplines (probiotic and biocontrol) and suggests sharing results from research via information technology, efficient collaboration, and the use of novel molecular biological tools to achieve the objective of probiotic antagonists. © 2018 Society of Chemical Industry     

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold‐hopping approach. Structure–activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time‐dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P‐glycoprotein (Pgp)‐mediated efflux. Compound 80 c [{(1S,6R)‐3‐(6,7‐difluoroquinoxalin‐2‐yl)‐3,8‐diazabicyclo[4.2.0]octan‐8‐yl}(4‐methyl‐[1,1′‐biphenyl]‐2‐yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium‐release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep‐promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.     

A Structural Rationale for N-Methylbicuculline Acting as a Promiscuous Competitive Antagonist of Inhibitory Pentameric Ligand-Gated Ion Channels

Bicuculline, a valued chemical tool in neurosciences research, is a competitive antagonist of specific GABA_A receptors and affects other pentameric ligand-gated ion channels including the glycine, nicotinic acetylcholine and 5-hydroxytryptamine type 3 receptors. We used a fluorescence-quenching assay and isothermal titration calorimetry to record low-micromolar dissociation constants for N-methylbicuculline interacting with acetylcholine-binding protein and an engineered version called glycine-binding protein (GBP), which provides a surrogate for the heteromeric interface of the extracellular domain of the glycine receptor (GlyR). The 2.4 Å resolution crystal structure of the GBP:N-methylbicuculline complex, sequence and structural alignments reveal similarities and differences between GlyR and the GABA_A receptor–bicuculline interactions. N-methylbicuculline displays a similar conformation in different structures, but adopts distinct orientations enforced by interactions and steric blocks with key residues and plasticity in the binding sites. These features explain the promiscuous activity of bicuculline against the principal inhibitory pentameric ligand-gated ion channels in the CNS.     

Novel Monocyclam Derivatives as HIV Entry Inhibitors: Design,Synthesis, Anti‐HIV Evaluation,and Their Interaction with the CXCR4 Co‐receptor

The CXCR4 receptor has been shown to interact with the human immunodeficiency virus (HIV) envelope glycoprotein gp120, leading to fusion of viral and cell membranes. Therefore, ligands that can attach to this receptor represent an important class of therapeutic agents against HIV, thus inhibiting the first step in the cycle of viral infection: the virus–cell entry/fusion. Herein we describe the in silico design, synthesis, and biological evaluation of novel monocyclam derivatives as HIV entry inhibitors. In vitro activity testing of these compounds in cell cultures against HIV strains revealed EC₅₀ values in the low micromolar range without cytotoxicity at the concentrations tested. Docking and molecular dynamics simulations were performed to predict the binding interactions between CXCR4 and the novel monocyclam derivatives. A binding mode of these compounds is proposed which is consistent with the main existing site‐directed mutagenesis data on the CXCR4 co‐receptor. Moreover, molecular modeling comparisons were performed between these novel monocyclams, previously reported non‐cyclam compounds from which the monocyclams are derived, and the well‐known AMD3100 bicyclam CXCR4 inhibitors. Our results suggest that these three structurally diverse CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor.