Introduction
MEN 10376 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2) is an analogue of Neurokinin A (NKA), which has a selective affinity to NK2 tachykinin receptor. Starting from the C-terminal heptapeptide fragment of NKA, NKA (4-10) retains the same agonist activity as parent compound with increased selectivity for NK-2 receptor, and extensive structure-activity studies led to the development of a series of antagonists containing three D-Trp residues, and the MEN 10376 is the most potent compound of this series. Compared to the NKA (4-10) sequence, MEN 10376 has a sequence in which a Tyr residue is present at position 5 and a Lys residue is present at position 10.
Biological Activity
Tachykinins are a family of peptides which share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. In mammals three peptides of this family, substance P, neurokinin A and neurokinin B have an established role as transmitters in the nervous systems. The researches have shown that MEN 10376 is found to be preferentially expressed in rabbit pulmonary artery and bronchus, guinea pig bronchus and human ileum and colon, and the role of the configuration of D-Trp8, D-Trp9 and of the charged residue in position 10 has been found crucial in determining the affinity and selectivity of MEN 10376. Affinities of MEN 10376, which is expressed as pA2, is 8.08 in rabbit pulmonary artery, and displays > 250-fold selectivity over NK1 (pA2 = 5.66, guinea pig ileum) and NK3 (Ki > 10 mM, guinea pig brain). MEN 10376 shows a good selectivity for the NK-2A receptor as compared to NK-2B receptor, with a 100-fold difference in affinity.
Function
NKA, a member of the tachykinin peptide family, is widely distributed in the mammalian central and peripheral nervous systems. In the latter, NKA exerts its biological effects mainly by activating the tachykinin NK2 receptor. Tachykinin NK2 receptor antagonists are potential candidates for the treatment of bronchial hyperreactivity, irritable bowel syndrome, cystitis and other pathological conditions putatively mediated by endogenous tachykinins. This has prompted the search for potent and selective NK2 receptor antagonists as drug candidates. Experiments on isolated bronchial tubes and isolated bladders in guinea pigs showed that the affinity of MEN 10376 for the NK2 receptor was much greater in the former than in the latter formulation, and it appears that MEN 10376 may be a very valuable tool to assess the biological role of tachykinins in vivo, thus extending the information to the specific role of NK2 receptors (and possibly NK2 receptor subtypes) in relevant physiological responses.
References
1. Maggi, C. A., Giuliani, S. A. N. D. R. O., Ballati, L. I. D. O., Lecci, A. L. E. S. S. A. N. D. R. O., Manzini, S. T. E. F. A. N. O., Patacchini, R. I. C. C. A. R. D. O & Giachetti, A. N. T. O. N. I. O. (1991). In vivo evidence for tachykininergic transmission using a new NK-2 receptor-selective antagonist, MEN 10,376. Journal of Pharmacology and Experimental Therapeutics, 257(3), 1172-1178.
2. Quartara, L., Patacchini, R., Giuliani, S., Renzetti, A. R., Rovero, P., & Maggi, C. A. (1992). N-terminal truncated analogs of men 10376 as tachykinin NK-2 receptor antagonists. Life sciences, 51(25), 1929-1936.
