QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.060814v2 309/1/193    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, L. Articles by Li, M. Search for Related Content PubMed PubMed Citation Articles by Huang, L. Articles by Li, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

CELLULAR AND MOLECULAR

NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-Benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: A New Selective Inhibitor of T-Type Calcium Channels

Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, Louisiana (L.H., B.M.K., J.T.T., M.L.); Department of Medicinal Chemistry, Novo Nordisk A/S, Måløv, Denmark (T.M.T., J.B.H.); Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (H.Z.); Department of Pharmacology, Medical College of Virginia, Richmond, Virginia (M.Z.); and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada (D.S.R.).

Mibefradil is a Ca²⁺ channel antagonist that inhibits both T-type and high-voltage-activated Ca²⁺ channels. We previously showed that block of high-voltage-activated channels by mibefradil occurs through the production of an active metabolite by intracellular hydrolysis. In the present study, we modified the structure of mibefradil to develop a nonhydrolyzable analog, (1S, 2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride (NNC 55-0396), that exerts a selective inhibitory effect on T-type channels. The acute IC₅₀ of NNC 55-0396 to block recombinant ₁G T-type channels in human embryonic kidney 293 cells was 7 µM, whereas 100 µM NNC 55-0396 had no detectable effect on high-voltage-activated channels in INS-1 cells. NNC 55-0396 did not affect the voltage-dependent activation of T-type Ca²⁺ currents but changed the slope of the steady-state inactivation curve. Block of T-type Ca²⁺ current was partially relieved by membrane hyperpolarization and enhanced at a high-stimulus frequency. Washing NNC 55-0396 out of the recording chamber did not reverse the T-type Ca²⁺ current activity, suggesting that the compound dissolves in or passes through the plasma membrane to exert its effect; however, intracellular perfusion of the compound did not block T-type Ca²⁺ currents, arguing against a cytoplasmic route of action. After incubating cells from an insulin-secreting cell line (INS-1) with NNC 55-0396 for 20 min, mass spectrometry did not detect the mibefradil metabolite that causes L-type Ca²⁺ channel inhibition. We conclude that NNC 55-0396, by virtue of its modified structure, does not produce the metabolite that causes inhibition of L-type Ca²⁺ channels, thus rendering it more selective to T-type Ca²⁺ channels.

Address correspondence to: Dr. Ming Li, Department of Pharmacology SL-83, 1430 Tulane Avenue, New Orleans, LA 70112. E-mail: mli{at}tulane.edu

This article has been cited by other articles:

				L. Zhang, L. P. Renaud, and M. Kolaj Properties of a T-Type Ca2+Channel-Activated Slow Afterhyperpolarization in Thalamic Paraventricular Nucleus and Other Thalamic Midline Neurons J Neurophysiol, June 1, 2009; 101(6): 2741 - 2750. [Abstract] [Full Text] [PDF]

				P. H. Bui, A. Quesada, A. Handforth, and O. Hankinson The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil Drug Metab. Dispos., July 1, 2008; 36(7): 1291 - 1299. [Abstract] [Full Text] [PDF]

				S. Liu and M. T. Shipley Multiple Conductances Cooperatively Regulate Spontaneous Bursting in Mouse Olfactory Bulb External Tufted Cells J. Neurosci., February 13, 2008; 28(7): 1625 - 1639. [Abstract] [Full Text] [PDF]

				J. T. Taylor, L. Huang, B. M. Keyser, H. Zhuang, C. W. Clarkson, and M. Li Role of high-voltage-activated calcium channels in glucose-regulated {beta}-cell calcium homeostasis and insulin release Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E900 - E908. [Abstract] [Full Text] [PDF]

				P. Isope and T. H. Murphy Low threshold calcium currents in rat cerebellar Purkinje cell dendritic spines are mediated by T-type calcium channels J. Physiol., January 1, 2005; 562(1): 257 - 269. [Abstract] [Full Text] [PDF]