Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives
Abstract
:1. Introduction
2. Voltage-Gated Calcium Channels
3. Physiological Roles of VGCCs in the Nervous System
4. L-type VGCCs in Psychiatric Disorders
5. VGCC Inhibitors in the Treatment of Parkinson’s Disease
6. The Potential of Pyrimidine-2,4,6-Triones (PYT) as CaV1.3 Selective Inhibitors
7. VGCCs Inhibitors in Pain Treatment
8. VGCCs in Seizure Disorders
9. VGCCs in Migraine
10. VGCCs in the Aging Brain
11. Summary
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Current Type | CaV Nomenclature | Specific Blocker | Gene | Main Physiological Role | Disease |
---|---|---|---|---|---|
L | CaV1.1 | DHP | CACNA1S | Excitation-contraction coupling in skeletal muscle, regulation of gene transcription | Hypokalemic periodic paralysis [5], normokalemic periodic paralysis; malignant hypothermia susceptibility [5] |
CaV1.2 | DHP | CACNA1C | Excitation-contraction coupling in cardiac muscle, regulation of gene transcription, endocrine secretion, spine and dendritic calcium signaling in neurons | Timothy syndrome [25,26,27,28,29], bipolar disorder [30,31], depressive disorder [32,33,34], schizophrenia [33,35,36,37,38,39], post-traumatic stress syndrome [40,41], Brugada syndrome (# 611875), cardiac Long QT syndrome [# 618447] | |
CaV1.3 | DHP | CACNA1D | Hearing, cardiac and neuronal pace-making activity, spine and dendritic calcium signaling in neurons | Deafness [42,43], autism [44], bipolar disorder [45,46], sinoatrial dysfunction (# 614896) | |
CaV1.4 | DHP | CACNA1F | Retinal neurotransmission | Congenital stationary night blindness [47,48], X-linked Cone-Rode dystrophy (# 300476), Aland Island eye disease (# 300600) | |
N | CaV2.1 | ω-conotoxin-GVIA | CACNA1A | Neurotransmitter release, somatodendritic calcium signaling | Familial hemiplegic migraine [49,50], ataxia (# 108500, # 183086) |
P/Q | CaV2.2 | ω-agatoxin-IVA | CACNA1B | Pain [8,51,52,53,54,55,56,57,58,59,60,61], neurodevelopmental disorder # 618497 | |
R | CaV2.3 | SNX-482 | CACNA1E | Neurotransmitter release, membrane excitability | Seizure [62,63,64,65], neurodevelopmental disorder(# 618497), encephalopathy (# 618285) |
T | CaV3.1 | Ethosuximide Zonisamide | CACNA1G | Membrane excitability, pace-making, firing, subthreshold oscillations | Seizure [66], spinocerebellar ataxia (# 616795 and # 618087) |
CaV3.2 | Ethosuximide Zonisamide | CACNA1H | Seizure [67,68,69,70,71,72], autism [73], pain [51,52,53,54], hyperaldosteronism (# 617027) | ||
CaV3.3 | Ethosuximide Zonisamide | CACNA1I | Seizure and neurodevelopmental disorders [74] |
Small Molecules | Approved Applications | Target | Potential Applications # |
---|---|---|---|
Isradipine | Hypertension | L-type channels | Autism [44,116], failed Phase-III trial for PD [116], dependency [151] |
Nimpodipine | Hypertension | L-type channels | Anxiety [121], febrile seizures [195] |
Roscovitine | NA | CaV1.2, L-type currents | Timothy syndrome [29,114] |
Pregabalin | Pain and seizures | CaVα2δ | Anxiety [119] |
Gabapentin | Pain and seizures | CaVα2δ | Anxiety [119] |
NNC 55-0396 | NA | T-type currents | PD [145] |
Valeriana jatamansi derived small molecules | NA | CaV2.2, CaV3.1 | Pain [167] |
Ziconotide | Pain | CaV2.2 | NA |
BTT-266, BTT-369 | NA | β binding domain on α1 | Pain [170] |
Ethosuximide | Seizures | T-type channels | Pain [185] |
Valproate | Seizures | T-type channels | PD [190,191] |
Zonisamide | Seizures | T-type channels | Pain and PD [191,192] |
NP118809 (or Z160) | NA | N-type channels | Pain [164,193] |
Z944 | NA | T-type channels | Seizures, pain [193] |
Lamotrigine | Seizures | R-type channels | Pain [62] |
Benzohydroquinone | NA | CaV2.1 | Familial hemiplegic migraine 1 [49] |
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Lanzetti, S.; Di Biase, V. Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives. Molecules 2022, 27, 1312. https://doi.org/10.3390/molecules27041312
Lanzetti S, Di Biase V. Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives. Molecules. 2022; 27(4):1312. https://doi.org/10.3390/molecules27041312
Chicago/Turabian StyleLanzetti, Stefano, and Valentina Di Biase. 2022. "Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives" Molecules 27, no. 4: 1312. https://doi.org/10.3390/molecules27041312