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Inhibition of canine (NCX1.1) and Drosophila (CALX1.1) Na(+)-Ca(2+) exchangers by 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157).
J Pharmacol Exp Ther. 2003 Sep; 306(3):1050-7.JP

Abstract

The electrophysiological effects of the benzothiazepine 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157) (CGP) were investigated on the canine (NCX1.1) and Drosophila (CALX1.1) plasmalemmal Na+-Ca2+ exchangers. These exchangers were selected for study because they show opposite responses to cytoplasmic regulatory Ca2+, thereby allowing us to examine the role of this regulatory mechanism in the inhibitory effects of CGP. CGP blocked Na+-Ca2+ exchange current mediated by both transporters with moderate potency (IC50 values = approximately 3-17 microM) compared with other recently reported blockers of Na+-Ca2+ exchange [e.g., 2-[4-[2,5-difluorophenyl) methoxy]phenoxy]phenoxy]-5-ethoxyaniline (KB-R7943) and 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (SEA0400)]. Experiments using alpha-chymotrypsin to remove autoregulation of Na+-Ca2+ exchange showed that block by CGP was reduced, suggesting that part of the effects of this drug may require intact ionic regulatory mechanisms. For NCX1.1, the inhibition produced by CGP was greater for outward Na+-Ca2+ exchange currents compared with inward currents. When CALX1.1 was examined, the extent of inhibition was similar for both inward and outward exchange currents. Although the extent and potency of CGP-mediated inhibition of Na+-Ca2+ exchange are less than those observed with SEA0400 and KB-R7943, our data demonstrate that CGP constitutes a novel class of plasmalemmal Na+-Ca2+ exchange inhibitors. Moreover, the widespread use of CGP as a selective mitochondrial Na+-Ca2+ exchange inhibitor should be reconsidered in light of these additional inhibitory effects.

Authors+Show Affiliations

Institute of Cardiovascular Sciences, University of Manitoba Faculty of Medicine, St Boniface Research Centre, Winnipeg, Manitoba, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12808003

Citation

Omelchenko, Alexander, et al. "Inhibition of Canine (NCX1.1) and Drosophila (CALX1.1) Na(+)-Ca(2+) Exchangers By 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157)." The Journal of Pharmacology and Experimental Therapeutics, vol. 306, no. 3, 2003, pp. 1050-7.
Omelchenko A, Bouchard R, Le HD, et al. Inhibition of canine (NCX1.1) and Drosophila (CALX1.1) Na(+)-Ca(2+) exchangers by 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157). J Pharmacol Exp Ther. 2003;306(3):1050-7.
Omelchenko, A., Bouchard, R., Le, H. D., Choptiany, P., Visen, N., Hnatowich, M., & Hryshko, L. V. (2003). Inhibition of canine (NCX1.1) and Drosophila (CALX1.1) Na(+)-Ca(2+) exchangers by 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157). The Journal of Pharmacology and Experimental Therapeutics, 306(3), 1050-7.
Omelchenko A, et al. Inhibition of Canine (NCX1.1) and Drosophila (CALX1.1) Na(+)-Ca(2+) Exchangers By 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157). J Pharmacol Exp Ther. 2003;306(3):1050-7. PubMed PMID: 12808003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of canine (NCX1.1) and Drosophila (CALX1.1) Na(+)-Ca(2+) exchangers by 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157). AU - Omelchenko,Alexander, AU - Bouchard,Ron, AU - Le,Hoa Dinh, AU - Choptiany,Platon, AU - Visen,Neeraj, AU - Hnatowich,Mark, AU - Hryshko,Larry V, Y1 - 2003/06/13/ PY - 2003/6/17/pubmed PY - 2003/10/4/medline PY - 2003/6/17/entrez SP - 1050 EP - 7 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 306 IS - 3 N2 - The electrophysiological effects of the benzothiazepine 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157) (CGP) were investigated on the canine (NCX1.1) and Drosophila (CALX1.1) plasmalemmal Na+-Ca2+ exchangers. These exchangers were selected for study because they show opposite responses to cytoplasmic regulatory Ca2+, thereby allowing us to examine the role of this regulatory mechanism in the inhibitory effects of CGP. CGP blocked Na+-Ca2+ exchange current mediated by both transporters with moderate potency (IC50 values = approximately 3-17 microM) compared with other recently reported blockers of Na+-Ca2+ exchange [e.g., 2-[4-[2,5-difluorophenyl) methoxy]phenoxy]phenoxy]-5-ethoxyaniline (KB-R7943) and 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (SEA0400)]. Experiments using alpha-chymotrypsin to remove autoregulation of Na+-Ca2+ exchange showed that block by CGP was reduced, suggesting that part of the effects of this drug may require intact ionic regulatory mechanisms. For NCX1.1, the inhibition produced by CGP was greater for outward Na+-Ca2+ exchange currents compared with inward currents. When CALX1.1 was examined, the extent of inhibition was similar for both inward and outward exchange currents. Although the extent and potency of CGP-mediated inhibition of Na+-Ca2+ exchange are less than those observed with SEA0400 and KB-R7943, our data demonstrate that CGP constitutes a novel class of plasmalemmal Na+-Ca2+ exchange inhibitors. Moreover, the widespread use of CGP as a selective mitochondrial Na+-Ca2+ exchange inhibitor should be reconsidered in light of these additional inhibitory effects. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12808003/Inhibition_of_canine__NCX1_1__and_Drosophila__CALX1_1__Na_+__Ca_2+__exchangers_by_7_chloro_35_dihydro_5_phenyl_1H_41_benzothiazepine_2_one__CGP_37157__ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12808003 DB - PRIME DP - Unbound Medicine ER -