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[en] A method is described for the synthesis of the racemic [methyl-d3] forms of the nicotine metabolites cis-3'-hydroxycotinine and trans-3'-hydroxycotinine. The key intermediate was [methyl-d3]-N-methylhydroxylamine, obtained from a selective hydrogenation of d3-nitro-methane. This intermediate was converted to [methyl-d3]-α-3-pyridyl-N-methylnitrone, which was condensed with methyl acrylate to give a mixture of isomeric isoxazolidines. The hydrogenolysis of this mixture afforded a 70:30 mixture of [methyl-d3] cis- and trans-3'-hydroxycotinine, from which the pure cis-isomer could be isolated by recrystallization from acetone. [Methyl-d3]-trans-3'-hydroxycotinine could be prepared in high yield from the cis-isomer via chiral inversion utilizing a Mitsunobu reaction, or by chromatographic separation from a mixture of the cis- and trans-3'-benzoyloxycotinine, followed by O-debenzoylation in methanolic NaOH. (author)
[en] This account describes how antibodies specific for nicotine and its metabolites and for various prostaglandins and their metabolites have been used to develop sensitive RIA's for these compounds. Thus far, antibodies have been prepared and RIA's developed for at least 100 other compounds of pharmacological importance. It has been calculated that an individual animal has the potential to produce antibodies that can recognize 107 and perhaps up to 108 diverse immunodominant moieties. Nature, therefore, has provided the pharmacologist and synthetic chemist with an analytical system of extraordinary specificity that can be adapted to the quantitative determination of a wide variety of pharmacologically active molecules. It is clear that RIA will be an important analytical tool in research as well as in the clinical laboratory
[en] A versatile method has been developed for the accurate (+-1 percent) determination of stable isotope enrichment, without the need for a computer. The required accuracy is achieved by a 60 Hz. ac sine wave sweep voltage superimposed upon the dc accelerating voltage of the mass spectrometer. By allowing m/e peaks to be displayed in real time on an oscilloscope, accurate focus conditions can be continuously monitored. The sweep range can be narrowed to exclude unwanted background ion current at the same nominal but different exact mass. A sample-and-hold circuit permits independent gain control of the data from separate A.V.A. channels so that even very small ion current ratios can be measured with high precision. The selected ion recording/voltage sweep system possesses the full analytical precision obtainable from computerized systems, and has been applied to a variety of biomedical and clinical problems
[en] The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from Shank3 at sub-atomic resolution. While the structure presents the canonical SH3 domain fold, the binding site for proline-rich peptides is not conserved. In line with this, no binding of Pro-rich sequences by the Shank3 SH3 domain was observed. Sequence comparisons indicate that all Shank isoforms have similarly lost the classical Pro-rich peptide binding site from the SH3 domain. Whether the corresponding site in the Shank SH3 domains has evolved to bind a non-poly-Pro target sequence is currently not known. Our work provides an intriguing example of the evolution of a well-characterized protein-protein interaction domain within the context of multi-domain protein scaffolds, allowing the conservation of structural features, but losing canonical functional sites. The data are further discussed in light of known mutations in the SH3 domain or its vicinity in the different Shank isoforms. - Highlights: • The SH3 domain from Shank3 was studied at sub-atomic resolution. • The Shank family has lost the canonical peptide-binding site of the SH3 domain. • The Shank SH3 domain may have lost or altered canonical SH3 domain functions.