10.1002/jps.2600750621
The research describes a facile synthesis method for glycol metabolites of phenethylamine drugs, including potential metabolites of psynephrine, epinephrine, octopamine, and normacromerine. The purpose of this study was to develop a general synthetic scheme that yields high quantities of these metabolites using readily available monosubstituted and disubstituted acetophenones, overcoming challenges such as dimerization and pinacol-pinacolone rearrangement inherent in aromatic glycol synthesis. The process involved alpha-bromination, displacement with acetate ion, and reduction with lithium aluminum hydride, resulting in yields ranging from 46 to 91%.
10.1021/jm00300a005
The research investigates the inhibitory effects of various substituted benzimidazoles on phenethanolamine N-methyltransferase (PNMT), an enzyme responsible for the final step in epinephrine biosynthesis. The study aims to identify compounds that can effectively inhibit PNMT, potentially offering new therapeutic strategies for conditions related to epinephrine regulation. The researchers synthesized a series of substituted benzimidazoles and tested their inhibitory effects in vitro on bovine adrenal PNMT. They found that compounds with a free amino group in the 2-position and with substituents like Cl, NO?, or CF? in the 5 or both 5 and 6 positions were the most potent inhibitors, achieving 18-55% inhibition of enzyme activity at 0.28 μg/ml. Several of these compounds also selectively lowered adrenal epinephrine levels in mice without significantly affecting norepinephrine levels when administered in vivo. The study concludes that substituted benzimidazoles hold promise as PNMT inhibitors, but further research is needed to explore their potential therapeutic applications and to understand the mechanisms behind their in vivo activity.
10.1007/s00044-010-9411-5
The research focuses on the design, synthesis, and evaluation of novel substituted-piperazine analogues for their antiplatelet aggregation activity, which is crucial for managing cardiovascular and thromboembolic diseases. The study involves the synthesis of new carbamoylpyridine and carbamoylpiperidine analogues containing a nipecotic acid scaffold, with a series of chemical reactions utilizing reactants such as nicotinoyl chloride, various aryl and aroyl-piperazines, alkyl or aroylhalides, and potassium carbonate. The synthesized compounds were evaluated for their inhibitory activity against platelet aggregation using different agonists like ADP, adrenaline, collagen, arachidonic acid, and ristocetin. The experiments included quaternization, catalytic hydrogenation, and molecular modeling investigations to understand the structure-activity relationship and the impact of lipophilicity on activity. The most active compounds identified were N1-[1-(4-bromobenzyl)-3-piperidino-carbonyl]-N4-(2-chlorophenyl)-piperazine hydrobromide (20) and 1,4-bis-[3-[N4-(2-chlorophenyl)-N1-(piperazino-carbonyl)]-piperidin-1-yl-methyl]-benzene dibromide (30), both exhibiting significant antiplatelet aggregating effects at a concentration of 0.06 μM. The analyses included NMR spectroscopy, mass spectrometry, and molecular docking studies to elucidate the compounds' structures and their interactions with the thrombin receptor.
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