A light stabilizer (Tinuvin 770) that elutes from polypropylene plastic tubes is a potent L-type Ca(2+)-channel blocker.
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.
Glossmann
H
H
Institute für Biochemische Pharmakologie, Innsbruck, Austria.
Hering
S
S
Savchenko
A
A
Berger
W
W
Friedrich
K
K
Garcia
M L
ML
Goetz
M A
MA
Liesch
J M
JM
Zink
D L
DL
Kaczorowski
G J
GJ
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D044182:Benzylisoquinolines; D001667:Binding, Competitive; D002121:Calcium Channel Blockers; D002460:Cell Line; D003652:Decanoic Acids / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism; D004110:Diltiazem / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D010880:Piperidines / Q000494:pharmacology*; D011126:Polypropylenes / Q000737:chemistry*; D011817:Rabbits; D013552:Swine; D014700:Verapamil / Q000378:metabolism
D000470:Alkaloids; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D003652:Decanoic Acids; D004095:Dihydropyridines; D010880:Piperidines; D011126:Polypropylenes; C009438:tetrandrine; C083752:Tinuvin 770; D014700:Verapamil; D004110:Diltiazem