Neurokinin NK receptor

Long-chain terpenes, SCH 60065 (11) and nine other related analogs, have been isolated from Acremonium sp. (Hedge et al., 1997). These compounds are neurokinin (NK) receptor inhibitors with IC50 values ranges of 2.5 -11 pM (NKi) and 6.8-16 pM (NK2). 

Numerous neurotransmitter receptors are located in the vomiting center, CTZ, and GI tract. Examples of such receptors include cholinergic and histaminic, dopaminergic, opiate, serotonin, neurokinin (NK), and benzodiazepine receptors. Theoretically, chemotherapeutic agents, their metabolites, or other emetic compounds trigger the process of emesis through stimulation of one or more of these receptors. 

P/neurokinin 1 (NK ) receptors. Aprepitant has little or no affinity for serotonin... 

Mechanism of Action Aselective human substance P and neurokinin-1 (NK,) receptor antagonist that inhibits chemotherapy-induced nausea and vomiting centrally in the... 

The actions of substance P and neurokinins A and are mediated by three G protein-coupled tachykinin receptors designated NK i, NK 2, and NK 3. Substance P is the preferred ligand for the NK receptor, the predominant tachykinin receptor in the human brain. However, neurokinins A and also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NKi receptors. All three receptor subtypes are coupled to inositol trisphosphate synthesis and calcium mobilization. 

FIGURE 5—70. Substance P and neurokinin 1 receptors, part 3. Shown here is how substance P is formed from gamma PPT-A. Thus, substance P can be formed from three proteins derived from the PPT-A gene, namely, alpha, beta, and gamma PPT-A (see also Figs. 5-68 and 5-69). When substance P is released from neurons, it prefers to interact selectively with the neurokinin 1 subtype of neurokinin receptor (Figs. 5-68 to 5-70). However, there is a mismatch in the brain between the locations of substance P and the NK-1 receptors, suggesting that substance P acts preferentially by volume neurotransmission at sites remote from its axon terminals rather than by classical synaptic neurotransmission. 

Neurokinin B and neurokinin B receptors. The third important member of the neurokinin neurotransmitter family is neurokinin B (NK-B). Like NK-A, it is a ten amino acid peptide (decapeptide). Six of the ten amino acids in NK-B are the same as in NK-A, and four of the last five amino acids in the N-terminal tail of NK-B are identical to substance P (Fig. 5-67). 

FIGURE 5—72. Neurokinin A and neurokinin 2 receptors, part 2. Shown here is the formation of NK-A from the gamma PPT-A protein. The beta and gamma PPT-A proteins are the grandparents of NK-A and are cut down to size just as described for substance P, eventually forming the peptide neurotransmitter NK-A. Neurokinin A specifically binds to the NK-2 receptor. As for substance P, there is a mismatch between this neurotransmitter and its receptor anatomically, suggesting the important role of nonsynaptic volume neurotransmission for NK-A as well. However, the anatomical distribution of NK-A is different from that of substance P, and the anatomical distribution of NK-2 receptors is different from that of NK-1 receptors. 

FIGURE 5—73. Neurokinin B and neurokinin 3 receptors. The third important member of the neurokinin neurotransmitter family is NK-B, which is formed from a gene, called PPT-B, which is different from the gene from which either substance P or NK-A is derived. However, the process of converting the PPT-B protein into NK-B is analogous to that already described for substance P and NK-A. Neurokinin B prefers its own unique receptors, called NK-3 receptors. Neurokinin B and its NK-3 receptors are also mismatched and are located in different anatomical areas from substance P, NK-A, and their NK-1 and NK-2 receptors, respectively. 

Neurokinin receptor ligands - there are two types of NK receptors in the brain. NK2 agonists have been found to be anxiogenic while the antagonists are anxiolytic at least in animal studies. Some NK1 antagonists have also been shown to be anxiolytic in experimental studies. 

Fig. 4.6 Neurokinin receptor agonist. Substance P is a potent NK receptor agonist. After extensive biological studies, the undecapeptide could be truncated to an active hexapeptide with an improved affinity constant of 11.7 nM. To identify the crucial binding position of the hexapeptide, an alanine scan has been performed. The greatest...

Clidinium bromide, another quaternary ammonium compound with antimuscarinic activity, is used in a fixed combination with chlordiazepoxide hydrochloride (2.5 mg of clidinium and 5 mg of chlordiazepoxide Librax) however, such combinations are of limited value in patients with IBS because of the risk of habituation and rebound withdrawal. Cimetropium is another antimuscarinic compound that reportedly is effective in patients with IBS. Otilonium bromide has been used extensively for patients with IBS in other parts of the world. It is an ammonium salt with antimuscarinic effects that also appears to block Ca + channels and neurokinin NK-2 receptors. Mebeverine hydrochloride is a derivative of hydroxybenzamide that appears to have a direct effect on the smooth-muscle cell, blocking K+ and Ca channels. It is widely used outside of the United States as an antispasmodic agent for patients with IBS. 

For assessment of the neurokinin 1 receptor antagonist (NK-IRA) on peritoneal adhesion formation, a laparotomy is performed through a midline incision, and four ischemic buttons, spaced 1 cm apart, are created on both sides of the parietal... 

Neurokinins (NK), members of the mammalian tachyldnins. They are widely distributed in the central and peripheral nervous systems, and the two neurokinins (NKA and NKB) act as neurotransmitters or neuromodulators. The biological actions on many tissues are mediated via specific G protein-coupled receptors. Among the three subtypes of NK receptors, NKi is the preferred receptor for substance P. Neurokinin A, NKA (also known as substance K, neurokinin a, and neuromedin L), H-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met -NH2, is the agonist for the NK2 receptor, whereas neurokinin B, NKB (also known as neurokinin and neuromedin K), H-Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met -NH2, mediates its action through the NK3 receptor. Together with substance P, the NK play an important role in pain transmission, neurogenic inflammation, smooth muscle contraction, secretion, vasodilation, and activation of the immune system. The NK were isolated from porcine spinal cord extracts and synthesized by Munekata and coworkers in 1984 [E. Munekata et al., Chem. Lett. 1984, 1013 K. Eolkers et al., Biochem. Biophys. Res. Commun. 1984, 118, 405 J. E. Maggio, Annu. Rev. Neurosci. 1988, 11, 13 Z. Gao,... 

Autoradiographic analysis has also revealed SP-binding sites in the cat carotid body (66). Neurokinin-1 receptor mediates the actions of SP elsewhere in the nervous system. Blockade of NK-1 receptors in the cat carotid body prevented... 

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