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Substance P belongs to the tachykinin family of peptides, which share the common carboxyl terminal sequence Phe-Gly-Leu-Met. Other members of this family are neurokinin A and neurokininB. Substance P is an undecapeptide, while neurokinins A and Bare decapeptides.
Substance P is present in the central nervous system, where it is a neurotransmitter , and in the gastrointestinal tract, where it may play a role as a transmitter in the enteric ner-vous system and as a local hormone .
Substance P is the most important member of the tachykinin family. It exerts a variety of incompletely understood central actions that implicate the peptide in behavior, anxiety, depression, nausea, and emesis. It is a potent arteriolar vasodilator, producing marked hypotension in humans and several animal species. The vasodilation is mediated by release of nitric oxide from the endothelium. Conversely, substance P causes contraction of venous, intestinal, and bronchial smooth muscle. It also stimulates secretion by the salivary glands and causes diuresis and natriuresis by the kidneys.
The actions of substance P and neurokinins A and B are medi-ated by three Gq protein-coupled tachykinin receptors designated NK1, NK2, and NK3. Substance P is the preferred ligand for theNK1 receptor, the predominant tachykinin receptor in the human brain. However, neurokinins A and B also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NK1 receptors. All three receptor subtypes are coupled to inositol trisphosphate synthesis and calcium mobilization.
Several nonpeptide NK1 receptor antagonists have been devel-oped. These compounds are highly selective and orally active, and enter the brain. Recent clinical trials have shown that these antagonists may be useful in treating depression and other disor-ders and in preventing chemotherapy-induced emesis. The first of these to be approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting is aprepitant . Fosaprepitant is a prodrug that is converted to aprepitant after intravenous administration and may be a useful parenteral alternative to oral aprepitant.
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