CYCLOSPORINE-A IS A SUBSTANCE-P (TACHYKININ NK1) RECEPTOR ANTAGONIST

The immunosuppressive cyclic undecapeptide, cyclosporin A, inhibited t he binding of [I-125]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 cyclo sporin A (dihydro-cyclosporin A) was an equally effective inhibitor, b ut the O-acetylated derivative (cyclosporin A-OAc) was 3-4-fold less p otent. The cyclosporin compounds also inhibited [I-125]neurokinin A bi nding to human NK2 receptors with potencies slightly less than at NK1 sites. In contrast, they were 8-20-fold less effective inhibitors of [ I-125]MePhe(7)-neurokinin B binding to guinea pig NK3 receptors (p < 0 .001). Thus, the cyclosporin A compounds showed selectivity for NK1 an d NK2 receptors The structure-activity pattern for the effects of cycl osporin A compounds at tachykinin receptors differs from the pattern p reviously described for their immunosuppressive activity. All three co mpounds inhibited substance P induced interleukin-6 (IL-6) secretion f rom U-373 MG astrocytoma cells with potencies similar to their NK1 rec eptor binding affinities. In addition, cyclosporin A blocked substance P induced phosphatidylinositol (PI) turnover in U-373 MG cells withou t blocking the corresponding response to histamine. This novel pharmac ological profile of the cyclosporin A compounds as NK1 receptor antago nists does not appear to correlate with other known in vitro cyclospor in A functions.