Guanidine Derivative ADS1017, a Potent Histamine H Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile.

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H and H receptors (HR and HR, respectively). Moreover, we also checked their intrinsic activity toward HR and muscarinic M, M, and M receptors (MR, MR, and MR, respectively). Since ADS1017 has been proved to be the most selective and highly potent H antagonist in our series, we chose it as the lead structure for further biological evaluation.

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.

Objective: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.

Illuminating Neuropeptide Y Y Receptor Binding: Fluorescent Cyclic Peptides with Subnanomolar Binding Affinity as Novel Molecular Tools.

The neuropeptide Y (NPY) Y receptor (YR), a member of the family of NPY receptors, is physiologically activated by the linear 36-amino acid peptide pancreatic polypeptide (PP). The YR is involved in the regulation of various biological processes, most importantly pancreatic secretion, gastrointestinal motility, and regulation of food intake. So far, YR binding affinities have been mostly studied in radiochemical binding assays.

Activation of Multiple G Protein Pathways to Characterize the Five Dopamine Receptor Subtypes Using Bioluminescence Technology.

G protein-coupled receptors show preference for G protein subtypes but can recruit multiple G proteins with various downstream signaling cascades. This functional selection can guide drug design. Dopamine receptors are both stimulatory (D-like) and inhibitory (D-like) with diffuse expression across the central nervous system.

The dark sides of the GPCR tree - research progress on understudied GPCRs.

A large portion of the human GPCRome is still in the dark and understudied, consisting even of entire subfamilies of GPCRs such as odorant receptors, class A and C orphans, adhesion GPCRs, Frizzleds and taste receptors. However, it is undeniable that these GPCRs bring an untapped therapeutic potential that should be explored further. Open questions on these GPCRs span diverse topics such as deorphanisation, the development of tool compounds and tools for studying these GPCRs, as well as understanding basic signalling mechanisms.

[H]UR-JG102-A Radiolabeled Cyclic Peptide with High Affinity and Excellent Selectivity for the Neuropeptide Y Y Receptor.

The family of human neuropeptide Y receptors (YRs) comprises four subtypes (YR, YR, YR, and YR) that are involved in the regulation of numerous physiological processes. Until now, YR binding studies have been predominantly performed in hypotonic sodium-free buffers using I-labeled derivatives of the endogenous YR agonists pancreatic polypeptide or peptide YY. A few tritium-labeled YR ligands have been reported; however, when used in buffers containing sodium at a physiological concentration, their YR affinities are insufficient.

Clonidine stimulates force of contraction via histamine H receptors in the human atrium.

Clonidine has various clinical effects mediated by agonism of α- or α-adrenoceptors and the blocking of hyperpolarization-activated-nucleotide-gated pacemaker channels (HCN). It is unknown whether clonidine can also stimulate human cardiac histamine H receptors (hHRs). We used isolated electrically stimulated left and spontaneously beating right atrial preparations from mice overexpressing the hHR specifically in the heart (H-TG), and spontaneously beating right atrial preparations of guinea pigs for comparison.

Stereochemistry-Driven Interactions of α,γ-Peptide Ligands with the Neuropeptide Y Y-Receptor.

The G-protein-coupled Y-receptor (YR) and its endogenous ligand, pancreatic polypeptide (PP), suppress appetite in response to food intake and, thus, are attractive drug targets for body-weight control. The C-terminus of human PP (hPP), T-R-P-R-Y-, penetrates deep into the binding pocket with its tyrosine-amide and di-arginine motif. Here, we present two C-terminally amidated α,γ-hexapeptides (/) with sequence -R-γ-CBAA-R-L-R-Y-, where γ-CBAA is the (1,2,3)-configured 2-(aminomethyl)-3-phenylcyclobutanecarboxyl moiety () or its mirror image ().

Dual Piperidine-Based Histamine H and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain.

In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, and , differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σRs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds.

Lysergic acid diethylamide stimulates cardiac human H histamine and cardiac human 5-HT-serotonin receptors.

Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT serotonin receptors and/or H histamine receptors. We studied isolated electrically stimulated left atrial preparations, spontaneously beating right atrial preparations, and spontaneously beating Langendorff-perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of the human 5-HT receptor (5-HT-TG) or of the H-histamine receptor (H-TG).

Ergometrine stimulates histamine H receptors in the isolated human atrium.

Ergometrine (6aR,9R)-N-((S)-1-hydroxypropan-2-yl)-7-methyl-4,6,6a,7,8,9-hexa-hydro-indolo-[4,3-fg]chinolin-9-carboxamide or lysergide acid β-ethanolamide or ergonovine) activates several types of serotonin and histamine receptors in the animal heart. We thus examined whether ergometrine can activate human serotonin 5-HT receptors (h5-HTR) and/or human histamine H receptors (hHR) in the heart of transgenic mice and/or in the human isolated atrium. Force of contraction or beating rates were studied in electrically stimulated left atrial or spontaneously beating right atrial preparations or spontaneously beating isolated retrogradely perfused hearts (Langendorff setup) of mice with cardiac specific overexpression of the h5-HTR (5-HT-TG) or of mice with cardiac specific overexpression of the hHR (H-TG) or in electrically stimulated human right atrial preparations obtained during cardiac surgery.

Isoforms of GPR35 have distinct extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway bias.

Within the intestine, the human G protein-coupled receptor (GPCR) GPR35 is involved in oncogenic signaling, bacterial infections, and inflammatory bowel disease. GPR35 is known to be expressed as two distinct isoforms that differ only in the length of their extracellular N-termini by 31 amino acids, but detailed insights into their functional differences are lacking. Through gene expression analysis in immune and gastrointestinal cells, we show that these isoforms emerge from distinct promoter usage and alternative splicing.

A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H Receptor.

The histamine H receptor (HR) is considered an attractive drug target for various neurological diseases. We here report the synthesis of UR-NR266, a novel fluorescent HR ligand. Broad pharmacological characterization revealed UR-NR266 as a sub-nanomolar compound at the HR with an exceptional selectivity profile within the histamine receptor family.

A G protein-coupled receptor dimer imaging assay reveals selectively modified pharmacology of neuropeptide Y Y1/Y5 receptor heterodimers.

The ability of G protein-coupled receptors (GPCRs) to form dimers, and particularly heterodimers, offers potential for targeted therapeutics with improved selectivity. However, studying dimer pharmacology is challenging, because of signaling cross-talk or because dimerization may often be transient in nature. Here we develop a system to isolate the pharmacology of precisely defined GPCR dimers, trapped by bimolecular fluorescence complementation (BiFC).