Modulators of CXCR4 and CXCR7/ACKR3 Function

Copyright © 2019 by The Author(s). The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the small-molecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio- and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENT: To investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors

Synthesis and enantioseparation of 1,4-dihydropyridine ring containing condensed heterocycles

Sintezētas 1,4-dihidropiridīn-6-merkaptoetiķskābes un 6-metilsulfanil-1,4-dihidropiridīn-3-karbonskābes, pētīta to diastereomēru kristalizācija ar cinhonīnu. Izstrādātas jaunu 1,4-dihidropiridīna gredzenu saturošu kondensētu N,S-heterociklu – 4,7-dihidrotiēno[2,3-b]piridīnu un 5,8-dihidropirido[3,2-e][1,3]tiazīn-2-imīnija hlorīdu kā potenciālo multirezistences modulatoru sintēzes metodes. Pielietojot lipāzi Amano PS un veicot acilēšanu ar vinilacetātu kinētiskās kontroles apstākļos, ar 85% enantiomēro pārākumu iegūts acilētais produkts – 6-aciloksietilsulfanil-1,4-dihidropiridīns un 1,4-dihidropiridīn- 6-merkaptoetanols (98% ee) kā neizreaģējošais substrāts. Enzīmu katalizēta 1,4-dihidropiridīn-6-merkaptoetanola acilēšana ar vinilacetātu ir jauna metode sēra saturošu 1,4-dihidropiridīnu sadalīšanai enantiomēros.1,4-Dihydropyridine-6-mercaptoacetic acids and 6-methylsulfanyl-1,4-dihydropyridine-3-carboxylic acids were synthesized and crystallization of their diastereomeric cinchonine salts was studied. Synthetic methods for the 1,4-dihydropyridine ring containing condensed N,S-heterocycles – 4,7-dihydrothieno[2,3-b]pyridines and 5,8-dihydro-2H-pyrido [3,2-e][1,3]thiazin-2-iminium chlorides as potential multidrug resistance modulators were developed. By making use of Amano PS lipase as catalyst kinetically controlled acylation with vinyl acetate proceeded with formation of 6-acyloxyethylsulfanyl-1,4-dihydropyridine in 85% enantiomeric excess and 1,4-dihydropyridine-6-mercaptoethanol as unreacted substrate (98% ee). Enzyme catalyzed acylation of 1,4-dihydropyridine-6-mercaptoethanol by making use of vinyl acetate is a new method for enantioseparation of sulfur-containing 1,4-dihydropyridines

5′-substituted amiloride derivatives as allosteric modulators binding in the sodium ion pocket of the adenosine A\u3csub\u3e2A\u3c/sub\u3e receptor

The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5′-substituted amiloride derivatives as hA2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [3H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([3H]ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA2AAR. 4-Ethoxyphenethyl-substituted amiloride 12l was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site

5′-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A_2A Receptor

The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride <b>1</b> and 5-(<i>N</i>,<i>N</i>-hexamethylene)­amiloride <b>2</b> (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A_2A receptor (hA_2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5′-substituted amiloride derivatives as hA_2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [³H]­4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]­triazolo­[1,5-<i>a</i>]-[1,3,5]­triazin-5-yl)­amino)­ethyl)­phenol ([³H]­ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA_2AAR. 4-Ethoxy­phenethyl-substituted amiloride <b>12l</b> was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site

5′-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A_2A Receptor

The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride <b>1</b> and 5-(<i>N</i>,<i>N</i>-hexamethylene)­amiloride <b>2</b> (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A_2A receptor (hA_2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5′-substituted amiloride derivatives as hA_2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [³H]­4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]­triazolo­[1,5-<i>a</i>]-[1,3,5]­triazin-5-yl)­amino)­ethyl)­phenol ([³H]­ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA_2AAR. 4-Ethoxy­phenethyl-substituted amiloride <b>12l</b> was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site