title: Cyclosporin A is a substance P (tachykinin NK1) receptor antagonist.
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.
authors.affiliation: Central Nervous System Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0403, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Gitter
authors.forename: D C
authors.initials: DC
authors.lastname: Waters
authors.forename: P G
authors.initials: PG
authors.lastname: Threlkeld
authors.forename: A M
authors.initials: AM
authors.lastname: Lovelace
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: R F
authors.initials: RF
authors.lastname: Bruns
mesh_terms: D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010716:Phosphatidylinositols / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism; D015320:Tachykinins / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D015850:Interleukin-6; D064729:Neurokinin-1 Receptor Antagonists; D010716:Phosphatidylinositols; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D015320:Tachykinins; D013373:Substance P; D006632:Histamine; D016572:Cyclosporine