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In a previous study we found that certain 3-phenylpiperidines (PPEs, 5) display a good activity at α2-adrenergic receptors (α2-AR ), whereas they are completely inactive at α1-AR. The PPEs 5 are conformationally restricted analogs of the corresponding adrenergic drug with a phenylethylamine structure (PAEs, 4) in which the benzylic hydroxyl group characteristic of the adrenergic catecholamines is not present. The most interesting of the PPEs proved to be the 3-(3,4-dimethylphenyl) substituted compound (5a) which had been found to be essentially inactive at β1- and β2-AR. The methyl groups present on the aromatic ring of 5a are found, albeit in a different position, on the phenyl of α2-adrenergic agonists with arylimidazolidine and arylimidazole structures. As such PPE 5a provided a unique template for the design of α2-AR ligands. On the basis of these premises, we synthesized all the possible dimethylphenyl-substituted isomers of PPE 5a. Their activity on α1- and α2-AR and on I1-imidazoline receptors (IR) was evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparation. Two selected PPEs, 5a and 5f, were also tested for their affinity on α2-AR subtypes. Conformational studies were carried out by means of theoretical calculations, in order to rationalise the results of pharmacological tests at the molecular level.

The protein substrate specificity of the catalytic subunit of rabbit skeletal muscle cyclic AMP-dependent protein kinase (EC 2.7.1.37; ATP:protein phosphotransferase) has been studied using genetic variants of beta casein. It was found that beta casein-B was phosphorylated at a much greater rate than beta caseins A1, A2, A3, or C. The enhanced phosphorylation of beta casein-B, as compared with the most common variant A2, was attributed to an arginine substitution for a serine at position 122, which caused a nearby residue, serine 124, to become a phosphorylation site for the protein kinase. These results further support the concept that the local primary structure is important in specificity and that arginine may be a specific determinant common to all the local phosphorylation site sequences recognized by the cyclic AMP-dependent protein kinase.

In deep review on the pharmacology and toxicology of diltiazem

Anemonia Sulcata Toxin II (ATX II) is a cardiotoxic peptide toxin from the coelenterate Anemonia viridis. Injected in mice, it induces arrhythmia and convulsions. In humans, the sea anemone sting usually causes only local pain and the formation of bullae. ATX II prolongs the inactivation of voltage-gated sodium (NaV) channels and induces the appearance of resurgent currents. ATX II proarrhythmic effect stands on the ability of the toxin to prolong action potential in cardiac myocytes and to reproduce the electrophysiological disturbances of long QT syndrome. ATX II also enhances persistent and resurgent Na + currents in dorsal root ganglia (DRG) neurons linked to A type and this could explain its ability to cause pain.