(1) Preparation of a Tritium-Labeled Intermediate for the Synthesis of a Tritiated IP Antagonist Prostacyclin (also known as prostaglandin 12 or PG12) is a labile metabolite of arachidonic acid produced in concert with the bis-enoic prostaglandins via the cyclooxygenase pathway. PG12 plays a major physiologic role as a potent mediator of vasodilation and inhibitor of platelet activation. Thus, PG12 causes relaxation of arterial smooth muscle and inhibition of platelet aggregation, degranulation, and shape change, and is therefore thought to be important in maintaining vascular homeostatis. The actions of PG12 are mediated via specific cell surface IP receptors, members of the G protein-coupled receptor gene superfamily, which upon activation cause an elevation in intracellular cAMP via direct stimulation of adenylate cyclase. The distribution of IP receptors mirrors the physiological actions of PG12. Studies in mice established that prostaglandin is an antithrombotic agent in vivo and provided evidence for its role as a mediator of inflammation and pain. It is possible to design synthetic molecules (antagonists) that can compete with the protein (a natural agonist) for binding to the receptors, thus preventing the agonist from delivering its message to the receptor and minimizing or eliminating the inflammatory processes. Roche researchers have designed and synthesized an antagonist for the IP receptor protein. TITLE: Preparation of Tritium-Labeled Intermediates (Continued) A 3H-labeled version of this antagonist with high specific activity (58 Ci/mmol) is required for receptor binding studies. This in turn requires the synthesis of a tritiated diphenylmethane intermediate from the tribromo derivative by catalytic reduction with tritium gas. (2) Preparation of a Tritium-Labeled Intermediate for the Synthesis of a Tritiated MCP-1 Antagonist Monocyte chemo attractant protein-1 (MCP-1) is a 76 amino acid protein belonging to the chemokine family and is considered to play a role in host defense and non-inflammatory disease states, including the development of atherosclerotic lesions through recruitment of blood monocyte and in the accumulation of macrophages in tumor sites. Biological activities attributed to MCP-1 include: monocyte chemotaxis, monocyte degranulation and respiratory burst activity, basophil chemotaxis, and histamine release. The specific effects of the chemokines on the target cells are mediated by G-coupled receptors. The MCP-1 receptor, a member of the seven transmembrane domain spanning family of receptors was shown to be highly specific for MCP, including the ability to respond to picomolar concentrations of MCP-1. Cell types known to express receptors for MCP-1 include monocytes, basophils and THP-1 monocytic cell line. It is possible to design synthetic molecules (antagonists) that can compete with the protein (a natural agonist) for binding to the receptors, thus preventing the agonist from delivering its message to the receptor and minimizing or eliminating the inflammatory processes. Roche scientists have designed and synthesized an antagonist for the MCP-1 protein. A 3H-labeled version of this antagonist with high specific activity (58 Ci/mmol) is required for receptor binding studies. This in turn requires the synthesis of tritiated p-tr if luoromethylphenylet hanol intermediat e f rom the ethy l ester by LiAlT4 reduction.
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