CGP 37157

CGP 37157 is a potent and selective antagonist of the mitochondrial Na+-Ca2+ exchanger with IC50 value of 0.4 μM [1].

The mitochondrial Na+-Ca2+ exchanger (mNCE) is an antiporter membrane protein and removes a single Ca2+ in exchange for the import of three Na+. Mitochondrial Ca2+ uptake plays a critical role in the control of apoptosis, regulation of metabolic activity and Ca2+ shaping and buffering of Ca2+ signals [2].

CGP 37157 is a selective mNCE antagonist. In isolated heart mitochondria, CGP-37157 inhibited the activity of mNCE with IC50 value of 0.36 μM in a dose-dependent way [1]. In human and mouse β-cells, CGP-37157 inhibited KCl- and glucose-stimulated Ca2+ signals in a dose-dependent way and decreased insulin secretion from perifused islets [2]. In rat forebrain neurons, CGP-37157 consistently caused a rapid fall in Ca2+ influx stimulated by glutamate, which suggested the recovery of Ca2+ influx induced by glutamate was regulated via mNCE [3]. In rat dorsal root ganglion neurons, CGP37157 inhibited depolarization-induced Ca2+ influx and mitochondrion-mediated Ca2+ influx [4].

References:
[1].  Cox DA, Conforti L, Sperelakis N, et al. Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157. J Cardiovasc Pharmacol, 1993, 21(4): 595-599.
[2].  Luciani DS, Ao P, Hu X, et al. Voltage-gated Ca(2+) influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP-37157. Eur J Pharmacol, 2007, 576(1-3): 18-25.
[3].  White RJ, Reynolds IJ. Mitochondria accumulate Ca2+ following intense glutamate stimulation of cultured rat forebrain neurones. J Physiol, 1997, 498 ( Pt 1): 31-47.
[4].  Baron KT, Thayer SA. CGP37157 modulates mitochondrial Ca2+ homeostasis in cultured rat dorsal root ganglion neurons. Eur J Pharmacol, 1997, 340(2-3): 295-300.

Voltage-gated Ca(2+) influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP-37157.[Pubmed:17719029]

Eur J Pharmacol. 2007 Dec 8;576(1-3):18-25.

Glucose-induced insulin release from pancreatic beta-cells relies largely on glucose metabolism and mitochondrial ATP synthesis. Inhibiting the mitochondrial Na(+)/Ca(2+) exchanger (mNCE) using 7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157) has been suggested to enhance ATP synthesis and insulin secretion from rat islets by promoting mitochondrial Ca(2+) accumulation. In this study we examined the effects of CGP-37157 on human and mouse islet cells. Surprisingly, we found that insulin secretion from perifused islets was reduced by CGP-37157. Cytosolic Ca(2+) measurements revealed that CGP-37157 dose-dependently blocked glucose- and KCl-stimulated Ca(2+) signals in both human and mouse beta-cells. Conversely, CGP-37157 induced mitochondrial hyperpolarization, NAD(P)H rises, and triggered diazoxide- and nifedipine-sensitive cytosolic Ca(2+) transients in a subset of quiescent cells bathed in sub-stimulatory glucose, which is in accord with metabolic activation by the compound. Hence, while blocking mNCE with CGP-37157 may augment metabolism of human and mouse beta-cells, the propagation of metabolic signals is hampered by simultaneous inhibition of voltage-gated Ca(2+) influx, and ultimately insulin secretion. Efforts to use CGP-37157 or design related compounds for therapeutic purposes should take these competing effects into account.

Inhibition of plasmalemmal Na(+)/Ca(2+) exchange by mitochondrial Na(+)/Ca(2+) exchange inhibitor 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157) in cerebellar granule cells.[Pubmed:14637198]

Biochem Pharmacol. 2003 Dec 15;66(12):2409-11.

In the heart, 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157) inhibits mitochondrial but not sarcolemmal Na(+)/Ca(2+) exchange. Therefore, CGP-37157 is often used as an experimental tool to study the role of mitochondrial Na(+)/Ca(2+) exchange in Ca(2+) homeostasis in various cells, including neurons. However, neurons express several K(+)-dependent (NCKX) and/or K(+)-independent (NCX) isoforms of plasmalemmal Na(+)/Ca(2+) exchange not expressed in the sarcolemma. Because it has never been determined whether CGP-37157 inhibits plasmalemmal NCKX and/or NCX isoforms in neurons, we tested this possibility. As an index of NCKX and/or NCX activity, we studied Na-dependent and gramicidin-induced 45Ca(2+) accumulation in the presence and absence of K(+), respectively. In primary cultures of cerebellar granule cells, CGP-37157 with IC(50) of 13 microM inhibited over 70% of plasmalemmal NCX activity (P<0.01) but not NCKX activity. Our data suggest that the effects of CGP-37157 on neuronal Ca(2+) homeostasis include inhibition of certain plasmalemmal NCX isoform(s). Because cerebellar granule cells robustly express NCX3 transcripts, which are not expressed in the heart, it appears that this isoform may be CGP-37157 sensitive.

Inhibition of L-type Ca2+ channel by mitochondrial Na+-Ca2+ exchange inhibitor CGP-37157 in rat atrial myocytes.[Pubmed:17054940]

Eur J Pharmacol. 2006 Dec 15;552(1-3):15-9.

7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepine-2(3H)-one (CGP-37157) inhibits mitochondrial Na(+)-Ca(2+) exchange. It is often used as an experimental tool for studying the role of the mitochondrial Na(+)-Ca(2+) exchanger in Ca(2+) signaling. Because the selectivity of CGP-37157 in adult cardiomyocytes has not been confirmed, we tested whether CGP-37157 affects the L-type Ca(2+) channel using a whole-cell patch-clamp in adult rat atrial myocytes. We found that CGP-37157 suppressed L-type Ca(2+) current (I(Ca)) with IC(50) of approximately 0.27 microM, without altering the voltage dependence of the current-voltage relationships. CGP-37157 inhibited the Ba(2+) current (I(Ba)) through the Ca(2+) channel with a similar dose-response. The inhibitory effects of CGP-37157 on I(Ca) or I(Ba) were resistant to the intracellular Ca(2+) buffering. Intracellular application of CGP-37157 did not significantly alter I(Ca). The combination of CGP-37157 with known Ca(2+) channel inhibitor diltiazem yielded antagonism consistent with additivity of response. Our data suggest that CGP-37157 directly suppresses the L-type Ca(2+) channel in intact adult cardiomyocytes.

CGP-37157 inhibits the sarcoplasmic reticulum Ca(2)+ ATPase and activates ryanodine receptor channels in striated muscle.[Pubmed:20923851]

Mol Pharmacol. 2011 Jan;79(1):141-7.

7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one [CGP-37157 (CGP)], a benzothiazepine derivative of clonazepam, is commonly used as a blocker of the mitochondrial Na+/Ca(2)+ exchanger. However, evidence suggests that CGP could also affect other targets, such as L-type Ca(2)+ channels and plasmalemma Na+/Ca(2)+ exchanger. Here, we tested the possibility of a direct modulation of ryanodine receptor channels (RyRs) and/or sarco/endoplasmic reticulum Ca(2)+-stimulated ATPase (SERCA) by CGP. In the presence of ruthenium red (inhibitor of RyRs), CGP decreased SERCA-mediated Ca(2)+ uptake of cardiac and skeletal sarcoplasmic reticulum (SR) microsomes (IC(5)(0) values of 6.6 and 9.9 muM, respectively). The CGP effects on SERCA activity correlated with a decreased V(max) of ATPase activity of SERCA-enriched skeletal SR fractions. CGP (>/= 5 muM) also increased RyR-mediated Ca(2)+ leak from skeletal SR microsomes. Planar bilayer studies confirmed that both cardiac and skeletal RyRs are directly activated by CGP (EC(50) values of 9.4 and 12.0 muM, respectively). In summary, we found that CGP inhibits SERCA and activates RyR channels. Hence, the action of CGP on cellular Ca(2)+ homeostasis reported in the literature of cardiac, skeletal muscle, and other nonmuscle systems requires further analysis to take into account the contribution of all CGP-sensitive Ca(2)+ transporters.

CGP37157 modulates mitochondrial Ca2+ homeostasis in cultured rat dorsal root ganglion neurons.[Pubmed:9537826]

Eur J Pharmacol. 1997 Dec 11;340(2-3):295-300.

The effects of 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-on (CGP37157), an inhibitor of mitochondrial Na+/Ca2+ exchange, on depolarization-induced intracellular free Ca2+ concentration ([Ca2+]i) transients were studied in cultured rat dorsal root ganglion neurons with indo-1-based microfluorimetry. A characteristic plateau in the recovery phase of the [Ca2+]i transient resulted from mitochondrion-mediated [Ca2+]i buffering. It was blocked by metabolic poisons and was not dependent on extracellular Ca2+. CGP37157 produced a concentration-dependent decrease in the amplitude of the mitochondrion-mediated plateau phase (IC50 = 4 +/- 1 microM). This decrease in [Ca2+]i was followed by an increase in [Ca2+]i upon removal of the drug, suggesting that Ca2+ trapped in the matrix was released when the CGP37157 was removed from the bath. CGP37157 also inhibited depolarization-induced Ca2+ influx at the concentrations required to see effects on [Ca2+]i buffering. Thus, CGP37157 inhibits mitochondrial Na+/Ca2+ exchange and directly inhibits voltage-gated Ca2+ channels, suggesting caution in its use to study [Ca2+]i regulation in intact cells.

Mitochondria accumulate Ca2+ following intense glutamate stimulation of cultured rat forebrain neurones.[Pubmed:9023766]

J Physiol. 1997 Jan 1;498 ( Pt 1):31-47.

1. In cultures of rat forebrain neurones, mitochondria buffer glutamate-induced, NMDA receptor-mediated Ca2+ influx. Here, we have used the fluorescent calcium indicator, indo-1 AM to record [Ca2+]i from single cells. We varied either the glutamate concentration or the duration of exposure to investigate the cellular mechanisms recruited to buffer [Ca2+]i within different stimulation protocols. 2. For a 15 s stimulus, the recovery time doubled as the glutamate concentration was raised from 3 to 300 microM. Changing the duration of exposure from 15 s to 5 min increased the recovery time tenfold even when the glutamate concentration was held at 3 microM. 3. We used a selective inhibitor of the mitochondrial Na(+)-Ca2+ exchange, CGP-37157. When applied immediately after a 15 s, 100 microM glutamate challenge, CGP-37157 consistently caused a rapid fall in [Ca2+]i followed by a slow rise after the drug was washed out. A similar pattern was seen with the 5 min, 3 microM glutamate stimulus. The effects of CGP-37157 are consistent with the release of substantial mitochondrial Ca2+ stores during recovery from an intense glutamate stimulus. 4. These studies suggest that mitochondria become progressively more important for buffering glutamate-induced Ca2+ loads as the stimulus intensity increases. The recovery of [Ca2+]i to baseline following glutamate removal is critically regulated by the release of Ca2+ from mitochondrial stores via mitochondrial Na(+)-Ca2+ exchange. The data highlight a previously under-appreciated role for [Na+]i in the regulation of [Ca2+]i in central neurones.

Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157.[Pubmed:7681905]

J Cardiovasc Pharmacol. 1993 Apr;21(4):595-9.

The objective was to determine if the benzothiazepine compound CGP-37157 selectively inhibits the Na(+)-Ca2+ exchanger of cardiac mitochondria without affecting the L-type voltage-dependent calcium channel, the Na(+)-Ca2+ exchanger, or the Na(+)-K(+)-ATPase of the cardiac sarcolemma, or the Ca(2+)-ATPase of the cardiac sarcoplasmic reticulum. Mitochondrial Na(+)-Ca2+ exchange activity was determined by monitoring intramitochondrial free [Ca2+] in isolated heart mitochondria loaded with the Ca(2+)-sensitive fluorophore fura-2. CGP-37157 inhibited the activity of mitochondrial Na(+)-Ca2+ exchange in a dose-dependent manner (IC50 0.36 microM). Calcium currents were recorded by whole-cell voltage clamp in isolated neonatal ventricular myocytes. Diltiazem was able to block the recorded current completely, thus confirming the current to be exclusively L-type. CGP-37157 had no effect on the calcium current recorded under identical conditions. CGP-37157, at concentrations < or = 10 microM, had no effect on the activities of the Na(+)-Ca2+ exchanger and Na(+)-K(+)-ATPase in isolated cardiac sarcolemmal vesicles or on activity of the Ca(2+)-ATPase in isolated cardiac sarcoplasmic reticulum vesicles. The data suggest that CGP-37157 is a potent, selective, and specific inhibitor of mitochondrial Na(+)-Ca2+ exchange at concentrations < or = 10 microM.

Modulation of intramitochondrial free Ca2+ concentration by antagonists of Na(+)-Ca2+ exchange.[Pubmed:8296399]

Trends Pharmacol Sci. 1993 Nov;14(11):408-13.

Evidence has accumulated in the past decade suggesting that Ca2+ acts as a second messenger not only in the cytosol of the heart to regulate contractility, but also within the mitochondria to regulate the rate of oxidative ATP synthesis. Just as elucidation of the second messenger pathways for Ca2+ in the cytosol has led to the development of pharmacological interventions that alter mechanical functioning of the heart, understanding the role of Ca2+ as a second messenger within the mitochondria and the mechanisms by which this organelle transports and regulates Ca2+ has exciting potential for developing pharmacological interventions that alter myocardial energy metabolism. In this article, David Cox and Mohammed Matlib discuss the potential consequences of pharmacologically increasing the intramitochondrial Ca2+ concentration on myocardial energy metabolism, and suggest some pathological conditions in which such an effect may be beneficial.

CGP37157 is a potent, selective inhibitor of Na+/Ca2+ exchanger, inhibiting the Na+-induced Ca2+-release from guinea-pig heart mitochondria, with an IC50 of 0.8 μM.

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