Neurokinin-2 (NK-2) receptors are found in smooth muscle of the respiratory, gastrointestinal and urogenital systems. NK-2 receptors activate the phosphoinositide pathway through a pertussis-toxin-insensitive G-protein. Several NK-2 receptor antagonists have been characterised that blocks NK2 receptor activity in vivo as well as in vitro model.
Natural ligand for Neuropeptide receptors NK-2 is neurokinin A (NKA). In the human intestine, the potent spasmogenic effect of tachykinins is mainly mediated by NK-2 receptors 1. NK2 receptor antagonists are fully effective in blocking nonadrenergic noncholinergic excitatory transmission in isolated human intestine 2,3. A series of 21 peptides were synthesized and tested in a variety of isolated organs in order to determine their potential as NK-2 antagonists. The peptides have been tested in the three monoreceptor systems, the dog carotid artery (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3) as well as on other preparations containing NK-2 receptors, such as the rat vas deferens, the hamster urinary bladder, the guinea-pig trachea and the human urinary bladder 4. The acetylaminoglycosidated bicyclic hexapeptide MEN 11420 (Nepadutant) is a potent and selective NK-2 receptor antagonists competitively binds with high affinity to the receptors 5,6. SR48968 is a selective NK-2 receptor antagonist SR48968 in behavioral, electrophysiological, and biochemical tests sensitive to the action of prototypical antidepressants (fluoxetine, imipramine) or to corticotropin-releasing factor (CRF) receptor antagonists 7.
Three compounds, of which two are linear peptides, Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2, Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg.NH2 and a cyclic one, cyclo[Gln-Trp-Phe-Gly-Leu-Met] have been tested in a variety of isolated organs in order to determine their potential as NK-2 antagonists. The first compound was found to be selective for the NK-2 receptor and showed only agonistic or no activity on the other receptor systems, while the second compound showed some antagonistic effects on the NK-2 and also on the other systems. The cyclic compound was found to be fairly selective for the NK-2 receptor 4. Two peptide antagonists are shown to be selective for NK2 receptor antagonists based on a screening programme with the rabbit pulmonary artery (RPA) bioassay system. The Structural characteristics of the peptides are Peptide I = [Tyr5, D-Trp68'9, Arg'0]-NKA; Peptide II = [Tyr5, D-Trp6'8 9, Arg'0]-NKA. Insertion of D-Trp in position 6, 8 and 9 on the backbone of the heptapeptide NKA yielded competitive antagonists for the NK2 receptor and further substitutions with Tyr in position 5 and Arg in position 10 increased both the affinity and selectivity of these antagonists. Peptide II differs from Peptide I in that the former conserves Thr in position 3, as present in the sequence of NKA 8.
Much effort has been directed to the development of synthetic antagonists capable of selectively blocking NK2 receptors, such as acetylaminoglycosidated bicyclic hexapeptide MEN 11420 (Nepadutant), SR48968 etc 5,6,7.
Mode of Action
The compound (Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2) was characterized as NK2 inhibitor. This compound exerted a competitive type of antagonism on the rabbit pulmonary artery and on the hamster urinary bladder. It was found to be inactive on receptors for acetylcholine, noradrenaline, angiotensin and des Arg9-bradykinin in the rabbit pulmonary artery 4.
The acetylaminoglycosidated bicyclic hexapeptide MEN 11420 (Nepadutant) has been demonstrated to be a potent, selective and competitive antagonist of tachykinin NK-2 receptors, both in animal and human preparations. In in vivo animal models, MEN 11420 produces an effective and long-lasting blockade of the NK-2 receptors expressed in the smooth muscle of the intestinal, genito-urinary and respiratory tract. In rats this antagonist activity is observed after several routes of administration, including intraduodenal, and the mean plasma half-life was found to be 44 min. MEN 11420 competitively binds with high affinity and specificity to the human NK2 receptor expressed in CHO cells. It selectively blocks NK-2 receptors on isolated smooth muscle preparations from animal and human tissues with pKB values in the range 8.1–10.2 5,6.
Peptide inhibitors of NK-2 receptor provide important tools for pharmacological studies on NK. They show competitive type of antagonism on the rabbit pulmonary artery and on the hamster urinary bladder 4.
SR48968 studies suggest that NK-2 receptor blockade may constitute a novel mechanism in the treatment of depression and CRF-related disorders 6.
MEN 11420, the NK-2 receptor antagonist MEN 11420 is capable of alleviating intestinal motor responses in humans evoked by infusion of NKA. Under basal conditions, MEN 11420 had no effect on motility indicating that tachykinins are not involved in the physiological regulation of the MMC via NK-2 receptors in man, but may be of importance in different disease states where increased motility is a predominating symptom 7.
1. Regoli D, Nantel F (1991). Pharmacology of neurokinin receptors. Biopolymers, 31:777–783.
2. Giuliani S, Barbanti G, Turini D, Quartara L, Rovero P, Giachetti A, Maggi CA (1991). NK-2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK-2 receptor subtype. Eur. J. Pharmacol., 203:365–370.
3. Zagorodnyuk V, Santicioli P, Turini D, Maggi CA (1997). Tachkykinin NK1 and NK2 receptors mediate NANC excitatory neuromuscular transmission in the human ileum. Neuropeptides, 31:265–271
4. Dion S, Rouissi N, Nantel F, Jukic D, Rhaleb NE, Tousignant C, Télémaque S, Drapeau G, Regoli D, Naline E (1990). Structure-activity study of neurokinins: antagonists for the neurokinin-2 receptor. Pharmacology, 41:184-194.
5. Catalioto RM, Criscuoli M, Cucchi P, Giachetti A, Gianotti D, Giuliani S, Lecci A, Lippi A, Patacchini R, Quartara L, Renzetti AR, Tramontana M, Arcamone F, Maggi CA (1998). MEN 11420 (Nepadutant) a novel glycosylated bicyclic peptide tachykinin NK-2 receptor antagonist. Br. J. Pharmacol., 123:81–91.
6. Catalioto RM, Cucchi P, Renzetti AR, Criscuoli M, Maggi CA (1998). Independent coupling of the human tachykinin NK2 receptor to phospholipases C and A2 in transfected chinese hamster ovary cells. Naunyn Schmiedeberg's Arch. Pharmacol., 358:395–403.
7. Steinberg R, Alonso R, Griebel G, Bert L, Jung M, Oury-Donat F, Poncelet M, Gueudet C, Desvignes C, Le Fur G, Soubrié P (2001). Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function. J Pharmacol Exp Ther., 299(2):449-458.
8. Maggi CA, Patacchini R, Giuliani S, Rovero P, Dion S, Regoli D, Giachetti A, Meli A (1990). Competitive antagonists discriminate between NK2 tachykinin receptor subtypes. Br. J. Pharmacol., 100:588-592.
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