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. 1993 Oct 15;90(20):9523–9527. doi: 10.1073/pnas.90.20.9523

A light stabilizer (Tinuvin 770) that elutes from polypropylene plastic tubes is a potent L-type Ca(2+)-channel blocker.

H Glossmann 1, S Hering 1, A Savchenko 1, W Berger 1, K Friedrich 1, M L Garcia 1, M A Goetz 1, J M Liesch 1, D L Zink 1, G J Kaczorowski 1
PMCID: PMC47601  PMID: 8415734

Abstract

A pharmacologically active agent was easily extracted by aqueous or organic solvents from laboratory plastic tubes (Falcon Blue Max) and has been chemically identified as bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate. This compound (approximately 12 micrograms per tube approximately 25 nmol) blocked 1,4-dihydropyridine-sensitive 45Ca2+ uptake into GH3 cells with an IC50 value of 3.6 microM, inhibited Sr2+ currents through L-type Ca2+ channels in A7r5 smooth-muscle cells in whole-cell patch-clamp experiments after extracellular application, and affected the high-affinity binding of Ca2+ entry-blocker ligands to a variety of preparations. Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate is a highly potent (IC50 values < 10 nM) inhibitor at the phenylalkylamine- and benzothiazepine-selective drug-binding domains of the alpha 1 subunit of L-type Ca2+ channels. This compound behaves as a heterotropic allosteric regulator for the 1,4-dihydropyridine-selective domain in purified Ca(2+)-channel preparations from rabbit skeletal muscle. (+)-Tetrandrine stimulation of 1,4-dihydropyridine binding to the membrane-bound L-type Ca2+ channel is inhibited by the compound in a competitive manner (Ki value = 6.8 nM). Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate is therefore classified as the prototype of another class of L-type Ca(2+)-channel blockers that binds to the alpha 1 subunit at the drug-binding domains selective for (+)-tetrandrine or (+)-cis-diltiazem. This compound is identical to Tinuvin 770, which is used worldwide as a light stabilizer for polyolefins.

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Selected References

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  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boer R., Grassegger A., Schudt C., Glossmann H. (+)-Niguldipine binds with very high affinity to Ca2+ channels and to a subtype of alpha 1-adrenoceptors. Eur J Pharmacol. 1989 May 11;172(2):131–145. doi: 10.1016/0922-4106(89)90004-7. [DOI] [PubMed] [Google Scholar]
  3. Catterall W. A. Functional subunit structure of voltage-gated calcium channels. Science. 1991 Sep 27;253(5027):1499–1500. doi: 10.1126/science.1654596. [DOI] [PubMed] [Google Scholar]
  4. Catterall W. A., Striessnig J. Receptor sites for Ca2+ channel antagonists. Trends Pharmacol Sci. 1992 Jun;13(6):256–262. doi: 10.1016/0165-6147(92)90079-l. [DOI] [PubMed] [Google Scholar]
  5. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  6. Garcia M. L., King V. F., Shevell J. L., Slaughter R. S., Suarez-Kurtz G., Winquist R. J., Kaczorowski G. J. Amiloride analogs inhibit L-type calcium channels and display calcium entry blocker activity. J Biol Chem. 1990 Mar 5;265(7):3763–3771. [PubMed] [Google Scholar]
  7. Garcia M. L., King V. F., Siegl P. K., Reuben J. P., Kaczorowski G. J. Binding of Ca2+ entry blockers to cardiac sarcolemmal membrane vesicles. Characterization of diltiazem-binding sites and their interaction with dihydropyridine and aralkylamine receptors. J Biol Chem. 1986 Jun 25;261(18):8146–8157. [PubMed] [Google Scholar]
  8. Garcia M. L., Trumble M. J., Reuben J. P., Kaczorowski G. J. Characterization of verapamil binding sites in cardiac membrane vesicles. J Biol Chem. 1984 Dec 25;259(24):15013–15016. [PubMed] [Google Scholar]
  9. Glossmann H., Ferry D. R. Assay for calcium channels. Methods Enzymol. 1985;109:513–550. doi: 10.1016/0076-6879(85)09112-1. [DOI] [PubMed] [Google Scholar]
  10. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  11. King V. F., Garcia M. L., Himmel D., Reuben J. P., Lam Y. K., Pan J. X., Han G. Q., Kaczorowski G. J. Interaction of tetrandrine with slowly inactivating calcium channels. Characterization of calcium channel modulation by an alkaloid of Chinese medicinal herb origin. J Biol Chem. 1988 Feb 15;263(5):2238–2244. [PubMed] [Google Scholar]
  12. King V. F., Garcia M. L., Shevell J. L., Slaughter R. S., Kaczorowski G. J. Substituted diphenylbutylpiperidines bind to a unique high affinity site on the L-type calcium channel. Evidence for a fourth site in the cardiac calcium entry blocker receptor complex. J Biol Chem. 1989 Apr 5;264(10):5633–5641. [PubMed] [Google Scholar]
  13. Knaus H. G., Moshammer T., Friedrich K., Kang H. C., Haugland R. P., Glossman H. In vivo labeling of L-type Ca2+ channels by fluorescent dihydropyridines: evidence for a functional, extracellular heparin-binding site. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3586–3590. doi: 10.1073/pnas.89.8.3586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Knaus H. G., Moshammer T., Kang H. C., Haugland R. P., Glossmann H. A unique fluorescent phenylalkylamine probe for L-type Ca2+ channels. Coupling of phenylalkylamine receptors to Ca2+ and dihydropyridine binding sites. J Biol Chem. 1992 Feb 5;267(4):2179–2189. [PubMed] [Google Scholar]
  15. McCarthy R. T., Cohen C. J. Nimodipine block of calcium channels in rat vascular smooth muscle cell lines. Exceptionally high-affinity binding in A7r5 and A10 cells. J Gen Physiol. 1989 Oct;94(4):669–692. doi: 10.1085/jgp.94.4.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Murphy T. H., Worley P. F., Baraban J. M. L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes. Neuron. 1991 Oct;7(4):625–635. doi: 10.1016/0896-6273(91)90375-a. [DOI] [PubMed] [Google Scholar]
  17. Nakayama H., Taki M., Striessnig J., Glossmann H., Catterall W. A., Kanaoka Y. Identification of 1,4-dihydropyridine binding regions within the alpha 1 subunit of skeletal muscle Ca2+ channels by photoaffinity labeling with diazipine. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9203–9207. doi: 10.1073/pnas.88.20.9203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Staudinger R., Knaus H. G., Glossmann H. Positive heterotropic allosteric regulators of dihydropyridine binding increase the Ca2+ affinity of the L-type Ca2+ channel. Stereoselective reversal by the novel Ca2+ antagonist BM 20.1140. J Biol Chem. 1991 Jun 15;266(17):10787–10795. [PubMed] [Google Scholar]
  19. Striessnig J., Murphy B. J., Catterall W. A. Dihydropyridine receptor of L-type Ca2+ channels: identification of binding domains for [3H](+)-PN200-110 and [3H]azidopine within the alpha 1 subunit. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10769–10773. doi: 10.1073/pnas.88.23.10769. [DOI] [PMC free article] [PubMed] [Google Scholar]

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