Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels

Eldo V. Kuzhikandathil, Gerry S. Oxford

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrochloride (SCH23390) is a widely used, highly selective antagonist of D1 dopamine receptors. While investigating the crosstalk between D1 and D3 dopamine receptor signaling pathways, we discovered that in addition to being a D1 receptor antagonist, SCH23390 and related compounds inhibit G protein-coupled inwardly rectifying potassium (GIRK) channels. We present evidence that SCH23390 blocks endogenous GIRK currents induced by either somatostatin or D3 dopamine receptors in AtT-20 cells (IC50, 268 nM). The inhibition is receptor-independent because constitutive GIRK currents in Chinese hamster ovary cells expressing only GIRK channels are also blocked by SCH23390. The inhibition of GIRK channels is somewhat selective because members of the closely related Kir2.0 family of inwardly rectifying potassium channels, as well as various endogenous cationic currents present in AtT-20 cells, are not affected. In addition, in current clamp recordings, SCH23390 can depolarize the membrane potential and induce AtT-20 cells to fire action potentials, indicating potential physiological significance of the GIRK channel inhibition. To identify the chemical features that contribute to GIRK channel block, we tested several structurally related compounds [SKF38393, R-(+)-7-chloro-8-hydroxy-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (nor- methyl-SCH23390), and R-(+)-2,3,4,5-tetrahydro-8-iodo-3- methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (iodo- SCH23390)], and our results indicate that the halide atom is critical for blocking GIRK channels. Taken together, our results suggest that SCH23390 and related compounds might provide the basis for designing novel GIRK channel-selective blockers. Perhaps more importantly, some studies that have exclusively used SCH23390 to probe D1 receptor function or as a diagnostic of D1 receptor involvement may need to be reevaluated in light of these results.

Original languageEnglish (US)
Pages (from-to)119-126
Number of pages8
JournalMolecular Pharmacology
Volume62
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

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G Protein-Coupled Inwardly-Rectifying Potassium Channels
Dopamine Antagonists
Dopamine D3 Receptors
Dopamine D1 Receptors
Benzazepines
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Inwardly Rectifying Potassium Channel
SCH 23390
1-phenyl-3-methyl-8-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine
Cricetulus
Somatostatin
Membrane Potentials
Action Potentials
Inhibitory Concentration 50
Ovary

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels",
abstract = "R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrochloride (SCH23390) is a widely used, highly selective antagonist of D1 dopamine receptors. While investigating the crosstalk between D1 and D3 dopamine receptor signaling pathways, we discovered that in addition to being a D1 receptor antagonist, SCH23390 and related compounds inhibit G protein-coupled inwardly rectifying potassium (GIRK) channels. We present evidence that SCH23390 blocks endogenous GIRK currents induced by either somatostatin or D3 dopamine receptors in AtT-20 cells (IC50, 268 nM). The inhibition is receptor-independent because constitutive GIRK currents in Chinese hamster ovary cells expressing only GIRK channels are also blocked by SCH23390. The inhibition of GIRK channels is somewhat selective because members of the closely related Kir2.0 family of inwardly rectifying potassium channels, as well as various endogenous cationic currents present in AtT-20 cells, are not affected. In addition, in current clamp recordings, SCH23390 can depolarize the membrane potential and induce AtT-20 cells to fire action potentials, indicating potential physiological significance of the GIRK channel inhibition. To identify the chemical features that contribute to GIRK channel block, we tested several structurally related compounds [SKF38393, R-(+)-7-chloro-8-hydroxy-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (nor- methyl-SCH23390), and R-(+)-2,3,4,5-tetrahydro-8-iodo-3- methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (iodo- SCH23390)], and our results indicate that the halide atom is critical for blocking GIRK channels. Taken together, our results suggest that SCH23390 and related compounds might provide the basis for designing novel GIRK channel-selective blockers. Perhaps more importantly, some studies that have exclusively used SCH23390 to probe D1 receptor function or as a diagnostic of D1 receptor involvement may need to be reevaluated in light of these results.",
author = "Kuzhikandathil, {Eldo V.} and Oxford, {Gerry S.}",
year = "2002",
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TY - JOUR

T1 - Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels

AU - Kuzhikandathil, Eldo V.

AU - Oxford, Gerry S.

PY - 2002

Y1 - 2002

N2 - R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrochloride (SCH23390) is a widely used, highly selective antagonist of D1 dopamine receptors. While investigating the crosstalk between D1 and D3 dopamine receptor signaling pathways, we discovered that in addition to being a D1 receptor antagonist, SCH23390 and related compounds inhibit G protein-coupled inwardly rectifying potassium (GIRK) channels. We present evidence that SCH23390 blocks endogenous GIRK currents induced by either somatostatin or D3 dopamine receptors in AtT-20 cells (IC50, 268 nM). The inhibition is receptor-independent because constitutive GIRK currents in Chinese hamster ovary cells expressing only GIRK channels are also blocked by SCH23390. The inhibition of GIRK channels is somewhat selective because members of the closely related Kir2.0 family of inwardly rectifying potassium channels, as well as various endogenous cationic currents present in AtT-20 cells, are not affected. In addition, in current clamp recordings, SCH23390 can depolarize the membrane potential and induce AtT-20 cells to fire action potentials, indicating potential physiological significance of the GIRK channel inhibition. To identify the chemical features that contribute to GIRK channel block, we tested several structurally related compounds [SKF38393, R-(+)-7-chloro-8-hydroxy-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (nor- methyl-SCH23390), and R-(+)-2,3,4,5-tetrahydro-8-iodo-3- methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (iodo- SCH23390)], and our results indicate that the halide atom is critical for blocking GIRK channels. Taken together, our results suggest that SCH23390 and related compounds might provide the basis for designing novel GIRK channel-selective blockers. Perhaps more importantly, some studies that have exclusively used SCH23390 to probe D1 receptor function or as a diagnostic of D1 receptor involvement may need to be reevaluated in light of these results.

AB - R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrochloride (SCH23390) is a widely used, highly selective antagonist of D1 dopamine receptors. While investigating the crosstalk between D1 and D3 dopamine receptor signaling pathways, we discovered that in addition to being a D1 receptor antagonist, SCH23390 and related compounds inhibit G protein-coupled inwardly rectifying potassium (GIRK) channels. We present evidence that SCH23390 blocks endogenous GIRK currents induced by either somatostatin or D3 dopamine receptors in AtT-20 cells (IC50, 268 nM). The inhibition is receptor-independent because constitutive GIRK currents in Chinese hamster ovary cells expressing only GIRK channels are also blocked by SCH23390. The inhibition of GIRK channels is somewhat selective because members of the closely related Kir2.0 family of inwardly rectifying potassium channels, as well as various endogenous cationic currents present in AtT-20 cells, are not affected. In addition, in current clamp recordings, SCH23390 can depolarize the membrane potential and induce AtT-20 cells to fire action potentials, indicating potential physiological significance of the GIRK channel inhibition. To identify the chemical features that contribute to GIRK channel block, we tested several structurally related compounds [SKF38393, R-(+)-7-chloro-8-hydroxy-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (nor- methyl-SCH23390), and R-(+)-2,3,4,5-tetrahydro-8-iodo-3- methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (iodo- SCH23390)], and our results indicate that the halide atom is critical for blocking GIRK channels. Taken together, our results suggest that SCH23390 and related compounds might provide the basis for designing novel GIRK channel-selective blockers. Perhaps more importantly, some studies that have exclusively used SCH23390 to probe D1 receptor function or as a diagnostic of D1 receptor involvement may need to be reevaluated in light of these results.

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