Ion channels as drug targets in central nervous system disorders

Abstract

Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na(+) channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 - for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca(2+)s channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca(v)1.1-Ca(v)3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

Fig. (1)

Schematic structure of VGSC.

Fig. (2)

Schematic arrangement of the α-and β-subunits of the VGSC. The pore is colored in red, the voltage sensors are yellow [according to: 2, 5].

Fig. (3)

Action potential of neuronal membrane in different functional states of VGSC.

Fig. (4)

Chemical structure of valproic acid.

Fig. (5)

Raised Ca²⁺ concentration in cell as a consequence of increased Na⁺ influx.

Fig. (6)

Simple presentation of binding sites of AEDs acting as sodium channels blockers in the Na_V1.2 homology model [46]. Aromatic ring has an aromatic-aromatic interaction with Tyr-1771, and amide, imide or amine moiety interacts with the aromatic ring of Phe-1764 by a low-energy amino-aromatic bond.

Fig. (7)

Chemical structure of phenytoin.

Fig. (8)

Chemical structure of carbamazpine.

Fig. (9)

Chemical structure of eslicarbazepine acetate.

Fig. (10)

Chemical structure of lamotrigine.

Fig. (11)

Chemical structure of JZP-4.

Fig. (12)

Chemical structure of lacosamide.

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Chemical structure of topiramate.

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Chemical structure of carisbamate.

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Chemical structure of rufinamide.

Fig. (16)

Chemical structure of flunarizine.

Fig. (17)

Chemical structure of riluzole.

Fig. (18)

Chemical structure of ranolazine.

Fig. (19)

Schematic arrangement of the α-and β-subunits of K_V channel characteristic for K_V1 and K_V4 subfamily. There are differences in position of β-subunit.

Fig. (20)

Chemical structure of retigabine.

Fig. (21)

Chemical structure of ICA-27243.

Fig. (22)

Chemical structure of 4-aminopyridine.

Fig. (23)

Schematic structure of calcium channels.

Fig. (24)

Tonic firing of neurons.

Fig. (25)

Low-threshold burst firing of neurons.

Fig. (26)

Thalamus-cortex circuitry.

Fig. (27)

Chemical structures of nifedipine, amlodipine, and nimodipine.

Fig. (28)

Chemical structure of pregabalin.

Fig. (29)

Chemical structure of gabapentin.

Fig. (30)

Chemical structure of 1-(2-methoxyphenyl)-3-[4-(1-methylsulfonyl)piperidinyl]-5-(4-chlorophenyl)pyrazol.

Fig. (31)

Chemical structures of ethosuximide and mesuximide.

Fig. (32)

Schematic structure of P2X receptor.

Fig. (33)

Chemical structure of suramin.

Fig. (34)

Chemical structure of CE-224535.

Fig. (35)

Schematic structure of NMDA receptor.

Fig. (36)

Chemical structure of gavestinel.

Fig. (37)

Chemical structure of selfotel.

Fig. (38)

Chemical structure of aptiganel.

Fig. (39)

Chemical structures of ifenprodil and Ro 25-6981.

Fig. (40)

Chemical structure of eliprodil.

Fig. (41)

Chemical structure of traxoprodil.

Fig. (42)

Chemical structure of Ro 63-1908.

Fig. (43)

Chemical structure of amantadine.

Fig. (44)

Chemical structure of memantine.

Fig. (45)

Chemical structure of dexanabinol.

Fig. (46)

Chemical structure of remacemide.

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Chemical structure of neramexane.

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Chemical structure of dimebon.

Fig. (49)

Chemical structure of cycloserine.

Fig. (50)

Chemical structure of felbamate.

Fig. (51)

(A) Schematic concentration of an ASIC unit, (B) Trimeric organization of a functional ASIC channel (TM1 and TM2 tramsmembrane domains 1 and 2) [272].

Fig. (52)

Chemical structure of benzamil.

Fig. (53)

Chemical structure of amiloride.

Fig. (54)

Chemical structure of A -317567.

Fig. (55)

Chemical structures of aromatic diamidines [305].

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Chemical structure of nafamostat.

Fig. (57)

Chemical structures of some NSAIDs.

Fig. (58)

PcTx1 binding site on ASIC1a channel.

Fig. (59)

Schematic structure of TRP channels [320].

Fig. (60)

Chemical structure of OAG.

Fig. (61)

Chemical structure of angiotensin II.

Fig. (62)

Chemical structure of thapsigargin.

Fig. (63)

Chemical structure of carbachol.

Fig. (64)

Chemical structure of pinokalant (LOE 908) [340, 341].

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Schematic structure of GABA_A receptor.

Fig. (66)

Chemical structure of SL651498.

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Chemical structure of MRK-409.

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Chemical structure of BL-1020.

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Chemical structure of L-838417.

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Chemical structure of TPA-023.

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Chemical structure of indiplon.

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Chemical structure of Y-23684.

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Chemical structure of CGP36742 or SGS742.

Fig. (74)

Chemical structures of cis-3-ACPBPA and trans-3- ACPBPA.