Linear Heptapeptide Antagonist, GR 94800



GR 94800, is a linear heptapeptide with the structure of PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Nle Amide, which is a highly potent and selective NK2 receptor antagonist. Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK2 receptor agonist potency and selectivity with respect to other neurokinin receptors. Further incorporation of Pro10, addition of a suitable lipophilic N-terminal substituent, and combined with further optimization of the N-terminal amino acids can provided the extremely potent and selective NK-2 antagonist GR 94800 (NK2 pKB = 9.6, NK1 pKB = 6.4, NK3 pKB = 6.0).

Biological Activity

In the assay of physiological and pharmacological characterization of the spinal tachykinin NK2 receptor, the action of GR 94800 was selective because the depolarizing effects of similar magnitude evoked by the NK1 receptor agonist [Sar9, Met(O2)11] substance P were not affected by GR 94800. The pA 2 values of GR 94800 amounted to 6.0±0.4 in the rat and 5.4±0.3 in the gerbil, and it was more potent in the rat than in the gerbil. The superfusion of GR 94800 (0.3-10 /μM) began 15 min before the application of the agonists and continued until the agonist-induced depolarization was terminated, and the pA2-value for GR 94800 was tested against the specific NK: receptor agonist was found to be 4.8±0.1. GR 94800 can develop its inhibitory effect within 15 min. The effect was of long duration and no recovery was observed within 60-90 min.


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, which has prompted the search for potent and selective NK2 receptor antagonists as drug candidates. For the treatment of irritable bowel syndrome, NK2 receptor, such as GR 94800, can inhibit intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models.


1. Carlo Alberto Maggi, Riccardo Patacchini, et al. Comparison of tachykinin NK1 and NK2 receptors in the circular muscle of the guinea-pig ileum and proximal colon. Br. J. Pharmacol, 1994, 112, 150-160.

2. Milvia Lepre, Hans -Rudolf Olpe, et al. Physiological and pharmacological characterization of the spinal tachykinin NK 2 receptor. European Journal of Pharmacology, 1994, 258, 23-31.

3. Andrew B. McElroy, Stephen P. Clegg, et al. Highly Potent and Selective Heptapeptide Antagonists of the Neurokinin NK-2 Receptor. J. Med. Chem., 1992, 35 ,2582-2591.

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