piperidines and tetrandrine

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.

Topics: Alkaloids; Animals; Benzylisoquinolines; Binding, Competitive; Calcium Channel Blockers; Cell Line; Decanoic Acids; Dihydropyridines; Diltiazem; Guinea Pigs; Heart; In Vitro Techniques; Piperidines; Polypropylenes; Rabbits; Swine; Verapamil

1. A series of substituted tetrahydroisoquinolins derived from the cleavage products of tetrandrine were found to inhibit [3H]-nitrendipine binding to rat cerebral cortical membranes. Those compounds which displaced [3H]-nitrendipine binding were also able to inhibit high KCl-induced contraction of rat aorta in vitro. 2. There was a significant correlation between the ability of these tetrahydroisoquinolines to inhibit [3H]-nitrendipine binding and KCl-induced contraction (r = 0.99, P less than 0.001). 3. CPU-23 (1-(1-[(6-methoxy)-naphth-2-yl])-propyl-2-(1-piperidine)-acetyl- 6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline), one of the most potent compounds identified in this series, behaved as a simple competitive inhibitor at the [3H]-nitrendipine binding site and reduced the apparent affinity but not the maximal number of binding sites in saturation analysis. 4. In contrast to nifedipine which caused hypotension and tachycardia, CPU-23 induced both hypotension and bradycardia in a dose-dependent manner in pentobarbitone-anaesthetized Sprague-Dawley rats, spontaneously hypertensive and age-matched normotensive WKY rats. 5. It is suggested that CPU-23 may exert its cardiovascular effects via interaction with the dihydropyridine binding site on the L-type calcium channel.

Topics: Alkaloids; Animals; Aorta; Benzylisoquinolines; Blood Pressure; Calcium Channels; Cerebral Cortex; Dose-Response Relationship, Drug; Female; Heart Rate; Hypertension; Isoquinolines; Male; Nitrendipine; Piperidines; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Tetrahydroisoquinolines; Vasoconstriction