Study of secondary and tertiary benzazepine derivatives Ca2+ channel blockers and their analog diltiazem

K. X. Li, M. Wakamori, S. D. Kimball, A. Schwartz

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Using two-microelectrode voltage-clamp techniques we investigated inhibitory effects of benzazepines (BZP, secondary derivatives, SQ3335I and SQ33537 and a tertiary derivative, SQ32910) and diltiazem on cloned L-type voltage-dependent Ca2+ channels. A rabbit heart <lC subunit in combination with α2a and β1b, subunits was expressed in Xenopus oocytes Current was carried by 40 mM Ba . The results are: 1) all secondary and tertiary BZP derivatives and diltiazem demonstrate a concentrationdependent inhibition of the current. The IC50 values are (in uM). SQ32910, 200; SQ33351, 250; SQ33537, 370; diltiazem, 500. This order is as same as that obtained in rabbit aortic strips with 100 mM KC1 by Floyd et al. (Floyd et al. J.Med. Chem. 1992, 35:756-772; Kimball et al. J.Med.Chem. 1992,35: 780-793); 2) The BZP derivatives and diltiazem do not shift the I-V relationship curves. The peak current is reached between +10 mV and +20 mV; 3) BZP derivatives show a use-dependence suggesting that they bind not only to the resting state but also to the open state of these channels; 4) The BZP derivatives shift the steady state inactivation curve to the left suggesting that they also bind to the inactivation state. These results demonstrate that these compounds have similar inhibitory effects on the recombinant L-type voltage-dependent Ca2+ channels. Further, it is probable that the drugs bind to an external site of the α1 subunit.

Original languageEnglish
Pages (from-to)A138
JournalFASEB Journal
Issue number3
Publication statusPublished - 1996 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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