Mepyramine 2% cream

Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon-carbon bonds in the pharmaceutical industry, the Suzuki-Miyaura cross-coupling reaction, often fails when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling process of unrivalled scope and utility is realized. The corresponding 3- and 4-substituted pyridine variants are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).

Abstract licence: CC BY-NC

There is a controversy whether histamine H1-receptor activation raises or lowers or does not affect contractility in the human heart. Therefore, we studied stimulation of H1-receptors in isolated electrically stimulated (one beat per second) human atrial preparations (HAP). For comparison, we measured force of contraction in left atrial preparations (LA) from mice with overexpression of the histamine H1-receptor in the heart (H1-TG). We detected the messenger ribonucleic acid (mRNA) expression of human histamine H1-receptors in HAP. In LA from H1-TG, each cumulatively applied concentration of histamine and a dual H1/H2-agonist called 2-(2-thiazolyl)-ethylamine (ThEA) caused a time-dependent initial negative inotropic effect followed over time by a lasting positive inotropic effect. Both effects were concentration-dependent in LA from H1-TG. After 100 µM cimetidine, 10 µM histamine exercised a positive inotropic effect in HAP that was diminished by 10 µM mepyramine, an H1-receptor antagonist. The concentrations of mepyramine and cimetidine used here are based on the work of others and our own work (e.g., Guo et al. J Cardiovasc Pharmacol. 6:1210-5 1984, Rayo Abella et al. J Pharmacol Exp Ther. 389:174-185 2024). Similarly, we observed that ThEA (10 µM, 30 µM, 100 µM cumulatively applied) induced a concentration- and time-dependent positive inotropic effect in HAP. In HAP, we detected never negative inotropic effects to either histamine or ThEA. The positive inotropic effects to ThEA in HAP were reduced by mepyramine. The positive inotropic effects of ThEA in LA from H1-TG and in HAP were not accompanied by reductions in the time of tension relaxation. We conclude that stimulation of histamine H1-receptors only increases and does not decrease force of contraction in the HAP in our patients.

Abstract licence: CC BY

The histamine H1-receptor (H1R) is an important mediator of allergy and inflammation. H1R antagonists have particular clinical utility in allergic rhinitis and urticaria. Here we have developed six novel fluorescent probes for this receptor that are very effective for high resolution confocal imaging, alongside bioluminescence resonance energy transfer approaches to monitor H1R ligand binding kinetics in living cells. The latter technology exploits the opportunities provided by the recently described bright bioluminescent protein NanoLuc when it is fused to the N-terminus of a receptor. Two different pharmacophores (mepyramine or the fragment VUF13816) were used to generate fluorescent H1R antagonists conjugated via peptide linkers to the fluorophore BODIPY630/650. Kinetic properties of the probes showed wide variation, with the VUF13816 analogues having much longer H1R residence times relative to their mepyramine-based counterparts. The kinetics of these fluorescent ligands could also be monitored in membrane preparations providing new opportunities for future drug discovery applications.

Abstract licence: CC BY