Distinct Properties of Amlodipine and Nicardipine Block of the Voltage-dependent Ca2+ Channels Cav1.2 and Cav2.1 and the Mutant Channels Cav1.2/dihydropyridine Insensitive and Cav2.1/dihydropyridine Sensitive

Overview

Journal Eur J Pharmacol

Specialty Pharmacology

Date 2011 Sep 14

PMID 21910984

Citations 9

Authors

Min Lin

Oluyemi Aladejebi

Gregory H Hockerman

Affiliations

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Abstract

The binding site within the L-type Ca(2+) channel Ca(v)1.2 for neutral dihydropyridines is well characterized. However, the contributions of the alkylamino side chains of charged dihydropyridines such as amlodipine and nicardipine to channel block are not clear. We tested the hypothesis that the distinct locations of the charged side chains on amlodipine and nicardipine would confer distinct properties of channel block by these two drugs. Using whole-cell voltage clamp, we investigated block of wild type Ca(v) 2.1, wild type Ca(v)1.2, and Ca(v)1.2/Dihydropyridine insensitive, a mutant channel insensitive to neutral DHPs, by amlodipine and nicardipine. The potency of nicardipine and amlodipine for block of closed (stimulation frequency of 0.05 Hz) Ca(v)1.2 channels was not different (IC(50) values of 60 nM and 57 nM, respectively), but only nicardipine block was enhanced by increasing the stimulation frequency to 1 Hz. The frequency-dependent block of Ca(v)1.2 by nicardipine is the result of a strong interaction of nicardipine with the inactivated state of Ca(v)1.2. However, nicardipine block of Ca(v)1.2/Dihydropyridine insensitive was much more potent than block by amlodipine (IC(50) values of 2.0 μM and 26 μM, respectively). A mutant Ca(v)2.1 channel containing the neutral DHP binding site (Ca(v)2.1/Dihydropyridine sensitive) was more potently blocked by amlodipine (IC(50)=41 nM) and nicardipine (IC(50)=175 nM) than the parent Ca(v)2.1 channel. These data suggest that the alkylamino group of nicardipine and amlodipine project into distinct regions of Ca(v)1.2 such that the side chain of nicardipine, but not amlodipine, contributes to the potency of closed-channel block, and confers frequency-dependent block.

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References

Pragnell M, Sakamoto J, Jay S, Campbell K . Cloning and tissue-specific expression of the brain calcium channel beta-subunit. FEBS Lett. 1991; 291(2):253-8. DOI: 10.1016/0014-5793(91)81296-k. View

Hui K, Kwok T, Kostelecki W, Leen J, Roy P, Feng Z . Differential sensitivities of CaV1.2 IIS5-S6 mutants to 1,4-dihydropyridine analogs. Eur J Pharmacol. 2008; 602(2-3):255-61. DOI: 10.1016/j.ejphar.2008.11.051. View

Liu G, Dilmac N, Hilliard N, Hockerman G . Ca v 1.3 is preferentially coupled to glucose-stimulated insulin secretion in the pancreatic beta-cell line INS-1. J Pharmacol Exp Ther. 2003; 305(1):271-8. DOI: 10.1124/jpet.102.046334. View

Iwanami M, Shibanuma T, Fujimoto M, Kawai R, TAMAZAWA K, Takenaka T . Synthesis of new water-soluble dihydropyridine vasodilators. Chem Pharm Bull (Tokyo). 1979; 27(6):1426-40. DOI: 10.1248/cpb.27.1426. View

Iwatsuki K, Iijima F, Chiba S . Secretory and vascular effects of the optical isomers of nicardipine. Clin Exp Pharmacol Physiol. 1984; 11(1):1-5. DOI: 10.1111/j.1440-1681.1984.tb00233.x. View

Dilmac N, Hilliard N, Hockerman G . Molecular determinants of Ca2+ potentiation of diltiazem block and Ca2+-dependent inactivation in the pore region of cav1.2. Mol Pharmacol. 2003; 64(2):491-501. DOI: 10.1124/mol.64.2.491. View

Kass R, Arena J, Chin S . Block of L-type calcium channels by charged dihydropyridines. Sensitivity to side of application and calcium. J Gen Physiol. 1991; 98(1):63-75. PMC: 2229044. DOI: 10.1085/jgp.98.1.63. View

Lacinova L, An R, Xia J, Ito H, Klugbauer N, Triggle D . Distinctions in the molecular determinants of charged and neutral dihydropyridine block of L-type calcium channels. J Pharmacol Exp Ther. 1999; 289(3):1472-9. View

Jones S . Overview of voltage-dependent calcium channels. J Bioenerg Biomembr. 1998; 30(4):299-312. DOI: 10.1023/a:1021977304001. View

10.

Hughes A, Wijetunge S . The action of amlodipine on voltage-operated calcium channels in vascular smooth muscle. Br J Pharmacol. 1993; 109(1):120-5. PMC: 2175575. DOI: 10.1111/j.1476-5381.1993.tb13540.x. View

11.

Hockerman G, Peterson B, Sharp E, Tanada T, Scheuer T, Catterall W . Construction of a high-affinity receptor site for dihydropyridine agonists and antagonists by single amino acid substitutions in a non-L-type Ca2+ channel. Proc Natl Acad Sci U S A. 1998; 94(26):14906-11. PMC: 25136. DOI: 10.1073/pnas.94.26.14906. View

12.

Kass R, Arena J . Influence of pHo on calcium channel block by amlodipine, a charged dihydropyridine compound. Implications for location of the dihydropyridine receptor. J Gen Physiol. 1989; 93(6):1109-27. PMC: 2216251. DOI: 10.1085/jgp.93.6.1109. View

13.

Cosconati S, Marinelli L, Lavecchia A, Novellino E . Characterizing the 1,4-dihydropyridines binding interactions in the L-type Ca2+ channel: model construction and docking calculations. J Med Chem. 2007; 50(7):1504-13. DOI: 10.1021/jm061245a. View

14.

Goldmann S, Stoltefuss J, Born L . Determination of the absolute configuration of the active amlodipine enantiomer as (-)-S: a correction. J Med Chem. 1992; 35(18):3341-4. DOI: 10.1021/jm00096a005. View

15.

Starr T, Prystay W, Snutch T . Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proc Natl Acad Sci U S A. 1991; 88(13):5621-5. PMC: 51929. DOI: 10.1073/pnas.88.13.5621. View

16.

Mitterdorfer J, Grabner M, Kraus R, Hering S, Prinz H, Glossmann H . Molecular basis of drug interaction with L-type Ca2+ channels. J Bioenerg Biomembr. 1998; 30(4):319-34. DOI: 10.1023/a:1021933504909. View

17.

Arrowsmith J, Campbell S, Cross P, Stubbs J, Burges R, Gardiner D . Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J Med Chem. 1986; 29(9):1696-702. DOI: 10.1021/jm00159a022. View

18.

Li H, Galue A, Meadows L, Ragsdale D . A molecular basis for the different local anesthetic affinities of resting versus open and inactivated states of the sodium channel. Mol Pharmacol. 1999; 55(1):134-41. DOI: 10.1124/mol.55.1.134. View

19.

Belciug M, Ananthanarayanan V . Interaction of calcium channel antagonists with calcium: structural studies on nicardipine and its Ca2+ complex. J Med Chem. 1994; 37(25):4392-9. DOI: 10.1021/jm00051a017. View

20.

Lee K, Tsien R . Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells. Nature. 1983; 302(5911):790-4. DOI: 10.1038/302790a0. View