T-channel blockers

Figure 2.1 Typical example of scaffold hopping, obtained by similarity screening with CATS descriptors. Starting from the left-hand reference T-channel blocker mibefradil, the right-hand compound clopimozid, a submicromolar T-channel blocker, is found among the 12 top ranking analogs.

Cavalli, A., Poluzzi, E., De Ponti, F., Recanatini, M. Toward a pharmacophore for drugs inducing the long QT syndrome Insights from a CoMFA study of HERG K-t channel blockers,... 

The calcium channel antagonists comprise the type EV antiarrhythmic category. At least two types of calcium channels are operative in SA and AV nodal tissues an L-type channel and a T-type channel. Therefore, both L-channel blockers (verapamil and diltiazem) and selective T-channel blockers (mibefradil—previously approved but withdrawn from the market) will slow conduction, prolong refrac-... 

The LVA ai subunits are blocked by moderate to low (10 pM) concentrations of nickel and bind the channel blocker mibefradil and kurotoxin. Both compounds are not specific LVA channel blockers because they block also Cavl. x and Cav2.x channels at about tenfold higher concentration. Interestingly, the endogenous cannabinoid anandamide binds to LVA channels and stabilises the inactivated state. This effect decreases T-type calcium current and neuronal firing activities. 

Tanabe, T., Takeshima, H., Mikami, A., Flockerzi, V., Takahashi, H., Kangawa, K., Kojima, M., Matsuo, H., Hirose, T., Numa, S. (1987). Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 328, 313-318. 

There is ample precedent for a modulatory role of K channels in behavior. The K channel blocker, 4-AP, selectively blocks component T (Bartschat and Blaustein 1985a). prolongs nerve action potentials, and enhances neurotransmitter release (Llinas et al. 1975). In man, intoxication with this agent may lead to dissociative behavior, agitation, confusion, convulsions, and coma (Spyker et al. 1980). However, the behavioral aberrations induced by 4-AP differ qualitatively from those induced by PCP. This implies that block of various types of presynaptic K channels may modify behavior and mental activity however, the precise nature of the behavioral manifestations is likely to depend upon the specific type of K channel that is affected. 

Patients with variant (Prinzmetal s) angina or cocaine-induced ACS may benefit from calcium channel blockers as initial therapy because they can reverse coronary vasospasm. /J-Blockers generally should be avoided in these situations because they may worsen vasospasm through an unopposed /T-blocking effect on smooth muscle. 

FIG. 5. SK currents in UBSM cells. (A) Original records of whole-cell currents recorded from a guinea-pig UBSM cell during a 100 ms depolarization from — 60 mV to +10 mV. Current is shown under baseline conditions (control), and after addition of the SK channel blocker apamin (100 nM). (B) The apamin-sensitive portion of the current in A is shown (SK current). Dotted lines indicated zero current. (From G.M. Herrera M.T. Nelson, unpublished observations.)... 

Nelson Gil Wier, in your paper with Mordy Blaustein, you applied Ca2+ channel blockers, the arteries relaxed and the waves continued, didn t they ... 

Ma, B., Prueksaritanont, T. and Lin, J.H. (2000) Drug interactions with calcium channel blockers possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metabolism and Disposition, 28 (2), 125-130. 

Anget T, Madge DJ, Mulla M, Riddall D, Medicinal Chemistty of Neuronal Voltage-Gated Sodium Channel Blockers,Chem 44 115—137, 2001. 

The available Ca channel blockers exert their effects primarily at voltage-gated Ca channels of the plasma membrane. There are at least several types of channels—L, T, N, P/Q and R—distinguished by their electrophysiological and pharmacological characteristics. The blockers act at the L-type channel at three distinct receptor sites (Fig. 19.2). These different receptor interactions underlie, in part, the qualitative and quantitative differences exhibited by the three principal classes of channel blockers. 

Kohno, T. Kim, J.I. Kobayashi, K. Kodera, Y. Maeda, T. Sato, K. (1995) Three-dimensional structure in solution of the calcium channel blocker u-conotoxin MVIIA. Biochemistry, 34, 10256-65. 

Anger, T., Madge, D. J., Mulla, M., Riddal, D. Medicinal chemistry of neuronal voltage-gated sodium channel blockers, J. Med. Chem. 2001, 44, 115-137. 

Atanassoff, P.G., Hartmannsgruber, M.W.B., Thrasher, J., Wermeling, D., Longton, W., Gaeta, R., Singh, T., Mayo, M., McGuire, D., Luther, R.R. Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain, Reg. Anesth. Pain Med. 2000, 25, 274-278. 

Bowersox, S.S., Gadbois, Th., Singh, T., Pettus, M., Wang, Y.-X., Luther, R.R. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX - 111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain, J. Pharmacol. Exper. Ther. 1996, 279, 1243-1249. 

Malmberg, A.B. and Yaksh, T.L. Effect of continuous intrathecal infusion of co-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats, Pain 1995, 60, 83-90. 

Malone, T.C., Schelkun, R.M., Yuen, P.-W. (Warner-Lambert Co ), Substituted phenols as novel calcium channel blockers, WO9705125 (1997). 

Miranda, H.F., Pelissier, T., Scierralta, F. Analgesic effects of intracerebroventricular administration of calcium channel blockers in mice, Gen. Pharmac. 1993, 24, 201-204. 

Monaghan, D. T. and Larsen, H. NR1 and NR2 subunit contributions to N-methyl-D-aspartate receptor channel blocker pharmacology, J. Pharmacol. Exp. Ther. 1997, 280, 614-620. 

The resolution of certain calcium channel blockers was optimized by temperature variations on cellulose tris(4-chlorophenylcarbamate) CSP coated on silica gel [150]. The van t Hoff plots for retention were curved, while those for selectivity were linear. 

Trebak, M., G. S. Bird, R. R. McKay and J. W. Putney, Jr., 2002, Comparison of human TRPC3 channels in receptor-activated and store-operated modes. Differential sensitivity to channel blockers suggests fundamental differences in channel composition, J Biol Chem, 277, (24), pp. 21617-21623 Tsiokas, L., T. Arnould, C. Zhu, E. Kim, G. Walz and V. P. Sukhatme, 1999, Specific association of the gene product of PKD2 with the TRPC1 channel, Proc Natl Acad Sci USA, 96, (7), pp. 3934-3939... 

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