(1) Preparation of tritium-labeled diphenylacetronitrile for the synthesis of a tritiated muscarinic antagonist Muscarinic receptors mediate the cellular actions of acetylcholine at the parasympathetic neuroeffector junction. In addition, these receptors mediate cholinergically mediated effects in the central nervous system (CNS), particularly in cortical and subcortical regions of the brain. Five muscarinic genes, m1 to m5 have been cloned, where m1, m2 and m3 appear to correspond to the pharmacological subtypes M1, M2 and M3 respectively. Muscarinic M3 antagonists are potentially useful as spasmolytics for the treatment of patients with various conditions involving smooth muscle spasms such as gastrointestinal motility disorders, functional diarrhea, irritable bowel syndrome, gastric and duodenal ulcers, spasms of the urinary tract and urinary incontinence. Researchers at Pfizer, Inc. have designed and synthesized a compound named Darifenacin for the treatment of urinary incontinence and irritable bowel disease. TITLE: Tritium Labelling of Muscarinic Antagonist and Analgesic Drug (Continued) Tritium-labeled Darifenacin with high specific activity is required for receptor binding studies. This in turn requires the synthesis of tritiated diphenylacetonitrile intermediate from polybrominated diphenylacetonitrile by catalytic reduction with tritium gas. (2) Preparation of a Tritium-Labeled Intermediate for the Synthesis of Tritiated CCR-3 Inhibitors: Synthesis of High Specific Activity 5-Bromotryptophol-3H The chemokines are a family of 8- to 12-kDa proteins that regulate leukocyte trafficking to specific seven-transmembrane-spanning G-protein-linked receptors. Regulation of these leukocytes can lead to remedies for treatment of asthma and allergy rhinitis. The CCR-3 inhibitor program has identified various antagonists of the chemokine receptor. High specific activity tritium labeled compounds are needed for receptor binding studies. Such high specific activity can be achieved by using LiAlT4 as reducing agent, on an appropriate intermediate. High specific activity LiAlT4 was prepared at the NTLF and was used to make 5-bromotryptophol-3H. Tritiated 5-bromotryptophol 2 was prepared when ketoester 1 reacted with LiAlT4 in refluxing THF. This afforded 4 Ci of tritiated product at 64% radiochemical purity (HPLC). The specific activity of the product was determined by an HPLC external standard method at 98-103 Ci/mmol. The high specific activity 5-bromotryptophol-3H will be converted to 5-carboxamido-tryptamine-3H (5-CT). 5-CT is a standard used in investigations of the 5-HT7 r eceptor pharmacology.
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