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  • Title: Cyclosporin A is a substance P (tachykinin NK1) receptor antagonist.
    Author: Gitter BD, Waters DC, Threlkeld PG, Lovelace AM, Matsumoto K, Bruns RF.
    Journal: Eur J Pharmacol; 1995 May 26; 289(3):439-46. PubMed ID: 7556412.
    Abstract:
    The immunosuppressive cyclic undecapeptide, cyclosporin A, inhibited the binding of [125I]substance P to tachykinin NK1 receptors expressed by human IM-9 lymphoblastoid cells, U-373 MG human astrocytoma cells and guinea pig lung parenchyma with IC50 values of 425 +/- 58, 783 +/- 180, and 784 +/- 163 nM respectively. The dihydro derivative of cyclosporin A (dihydro-cyclosporin A) was an equally effective inhibitor, but the O-acetylated derivative (cyclosporin A-OAc) was 3-4 fold less potent. The cyclosporin compounds also inhibited [125I]neurokinin A binding to human NK2 receptors with potencies slightly less than at NK1 sites. In contrast, they were 8-20-fold less effective inhibitors of [125I]MePhe7-neurokinin B binding to guinea pig NK3 receptors (p < 0.001). Thus, the cyclosporin A compounds showed selectivity for NK1 and NK2 receptors. The structure-activity pattern for the effects of cyclosporin A compounds at tachykinin receptors differs from the pattern previously described for their immunosuppressive activity. All three compounds inhibited substance P induced interleukin-6 (IL-6) secretion from U-373 MG astrocytoma cells with potencies similar to their NK1 receptor binding affinities. In addition, cyclosporin A blocked substance P induced phosphatidylinositol (PI) turnover in U-373 MG cells without blocking the corresponding response to histamine. This novel pharmacological profile of the cyclosporin A compounds as NK1 receptor antagonists does not appear to correlate with other known in vitro cyclosporin A functions.
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