Receptor Tachykinin

H-Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2. Physalaemin, eledoisin, kassinin, SCYl, and SCYll are nonmammalian tachykinins. Two larger peptides have been identified, neuropeptide K (328) and neuropeptide y (329), both of which interact with tachykinin receptors (Table 19). The NKA sequence is contained within the carboxy-terrninal sequences of both neuropeptide K and neuropeptide y. Like other neuroactive peptides, tachykinin peptide precursors are synthesized ribosomaHy and transported to nerve terminals where further processing occurs. 

Three tachykinin GPCRs, NK, NK, and NK, have been identified and cloned. AH are coupled to phosphatidjhnositol hydrolysis. The NK receptor is selective for substance P (SP) and is relatively abundant in the brain, spinal cord, and peripheral tissues. The NK receptor is selective for NKA and is present in the gastrointestinal tract, urinary bladder, and adrenal gland but is low or absent in the CNS. The NIC receptor is selective for NKB and is present in low amounts in the gastrointestinal tract and urinary bladder, but is abundant in some areas of the CNS, ie, the spinal dorsal bom, soUtary nucleus, and laminae IV and V of the cortex with moderate amounts in the interpeduncular nucleus. Mismatches in the distribution of the tachykinins and tachykinin receptors suggest the possibility of additional tachykinin receptor subtypes. 

C-fibre afferents from the aitways contain peptide tachykinin transmitters such as substance P (SP) and neurokinins A and B (NKA and NKB). Stimulation of these nerves can also cause local release of these mediators at their peripheral terminal, allowing them to enhance the activity of the RARs. SP, NKA and NKB act at the tachykinin receptors (NK4-NK3), and so understandably, antagonists for NK2 in particular appear promising in cough. 

The common C-terminal amino acid sequence required for exerting activity at tachykinin receptors is shown in bold endokinin C and D lack the C-terminal Met and are almost devoid of affinity at these receptors. In red, the sequence of neurokinin A of which neuropeptide-gamma and neuropeptide-kappa are elongated forms and neurokinin A (3-10) is a product of beta or gamma-TAC1 mRNAs or an NKA metabolite active at tachykinin receptors. In blue, the sequence of human HK-1 of which endokinin A and B are elongated forms. 

Tachykinins and their Receptors. Table 6 Examples of selective and non-selective tachykinin receptor antagonists... 

Almeida TA, Rojo J, Nieto PM et al (2004) Tachykinin and tachykinin receptors structure activity relationships. Curr MedChem 11 2045-2081... 

Lecci A (2003) Pharmacology and function of tachykinin receptors. Tocris Reviews 24 1—11... 

Tachykinin receptors Colonic carcinomas, astrocytomas, lymphomas... 

GPR19,GPR83 Peptides Tachykinin receptors ligands... 

Culman J, Wiegand B, Spitznagel H, Klee S, Unger T (1995) Effects of the tachykinin NKl receptor antagonist, RP 67580, on central cardiovascnlar and behavionral effects of snbstance P, neimokinin A and nenrokinin B. Br J Pharmacol 114 1310-1316 Cnlman J, Klee S, Ohlendorf C, Unger T (1997) Effect of tachykinin receptor inhibition in the brain on cardiovascular and behavioral responses to stress. J Pharmacol Exp Ther 280 238-246... 

Teixeira RM, De lima TC (2003) Involvement of tachykinin NKl receptor in the behavioral and immunological responses to swimming stress in mice. Nemopeptides 37 307-315 Teixeira RM, Santos AR, Ribeiro SJ, Calixto JB, Rae GA, De Lima TC (1996) Effects of central administration of tachykinin receptor agonists and antagonists on plus-maze behavior in mice. Em J Pharmacol 311 7-14... 

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. 

Table 1 Non-peptide antagonists for tachykinin receptors (adapted from Betancur et al.,1997). ...

It should be mentioned here that discovery of the tachykinin receptor antagonists has not been limited to the NKi receptor, as non-peptide antagonists for the NK2 receptor (e.g SR48.968) and NK3 receptor (e.g. SR142.801) are known. 

Furthermore, the discovery of novel compounds with higher therapeutic potential can be foreseen. A selection of compounds which were filed recently for the treatment of pain and migraine is given below. As all of the nonpeptide tachykinin receptor antagonists arose from... 

Durette, P., Kopka, I., MacCoss, M., Mills, S., (Merck Co.) Heteroaryl spiroethercycloalkyl tachykinin receptor antagonists, EP 5929094 (1999). 

Lecci, A., Giuliani, S., Patacchini, R., Viti, G, Maggi, C. A. Role ofNKl tachykinin receptors in... 

Nakajima, Y., Tsuchida, K., Negishi, M., Ito, S., Nakanishi, S. Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells, J. Biol. Chem. 1992, 267, 2437-2442. 

Nakanishi, S. Mammalian tachykinin receptors, Annu. Rev. Neurosci. 1991, 14, 123-136. 

Walpole, C., Ko, S. Y., Brown, M., Beattie, D., Campbell, E., Dickenson, F., Ewan, S., Hughes, G. A., Lemaire, M., Lerpiniere, J., Patel, S., Urban, L. 2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models, J. Med. Chem. 1998b, 41, 3159-3173. 

Maggi CA, Patacchini R, Eglezos A et al. (1992) Tachykinin receptors in the guinea pig renal pelvis Activation by exogenous and endogenous tachykinins. Br J Pharmacol 107 27-33... 

Burcher, E., Zeng, X. P., Strigas, J., Geraghty, D. P., and Lavielle, S. 1995. Tachykinin receptors in guinea-pig airways characterization using selective ligands. Can. J. Physiol. Pharm., 73(7), 915-922. 

Yuan, L., Burcher, E., and Nail, B. S. 1998. Characterization of tachykinin receptors mediating bronchomotor and vasodepressor responses to neuropeptide y and substance P in the anesthetized rabbit. Pulmon. Pharma. Therap.,ll(l), 31-39. 

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