Tachykinin antagonist. I: Specific, competitive and tissue-selective neurokinin B antagonists on contractile activity in smooth muscles.

Abstract

[3][4][5][6][7][8][9][10], were tested for agonistic activity as well as for their ability to antagonize the myotropic actions of NKB, neurokinin A, substance P, physalaemin and eledoisin in isolated guinea-pig ileum, guinea-pig urinary bladder, rat duode num, rat vas deferens and rat portal vein.[GIy6]-NKB [3][4][5][6][7][8][9][10] in the guinea-pig ileum and rat portal vein and [Arg3, D-Ala6]-NKB [3][4][5][6][7][8][9][10] in the guinea-pig ileum were found to be the first specific and competitive antagonists against NKB.

Pharmacological analysis of [3H]‐senktide binding to NK3 tachykinin receptors in guinea‐pig ileum longitudinal muscle‐myenteric plexus and cerebral cortex membranes

“…This is in good agreempnt with the rank order of potencies observed for these peptides in the rat portal vein (Mastrangelo et al, 1986; or the neuronal NK3 receptor bioassay in the guinea-pig ileum (Laufer et al, 1985 with the relative potencies obtained for these analogues in the rat portal vein bioassay 30pm. This is in contrast to its antagonist activity against NKB in the guinea-pig ileum, but consistent with its lack of antagonist activity in the rat portal vein (Hashimoto et al, 1987 (Featherstone et al, 1986;McKnight et al, 1988).…”

“…The non-selective NK1/NK2 antagonist [D-Pro4,D-Trp7'9'10]SP(4-11) (Featherstone et al, 1986) (Hashimoto et al, 1987) were similarly weakly active or inactive respectively.…”

Neurokinin-3 receptor antagonists

“…The first example reported, [Gly 6 ]-NK-B(3-10), antagonised NK-B-induced responses in the guinea-pig ileum preparation with a moderate potency (pA2 of 5.8) [48]; this action appeared to be NK3 receptor-selective, since SP-or NK-A-induced responses were not antagonised. A significant increase in the antagonist potency was achieved through chemical modifications in the partial sequences NK-A(4-10) and NK-B(4-10).…”

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

“…Several agonists derived for the NK3R have been obtained by modification of the primary structure of NKB [11]. [MePhe 7 ]NKB, a classical synthetic agonist, has been used extensively to study the role of NK3R and [Gly 6 ]NKB[3–10] has been used to facilitate the study of putative NK3R antagonists [12, 13]. Studies with chimeric NK1/NK3 receptors have identified that the carboxyl terminal domain, part of the third extracellular loop and the seventh transmembrane region of the NK3R, is important for NKB binding [14].…”