Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives

Abstract

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson's disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.

Keywords: CaV1; CaV2; CaV3; Compound 8; PYT; anxiety; autism spectrum disorders; gabapentin; pain; pregabalin; seizure; small molecules; splice variants; voltage-gated calcium channels.

Figure 1

The topology of voltage-gated calcium channels with known drug-binding regions and the mechanisms of channel inhibition. The image represents the channel complex including the Ca_Vα₁ pore forming subunit with the auxiliary Ca_Vβ and Ca_Vα2δ which regulate channel trafficking and biophysical properties. The Ca_Vα₁ is organized in four transmembrane domains (I–IV), each containing six membrane-spanning helices (S1–S6). All S5-S6 segments form the channel pore (P) whereas the S1-S4 constitute the voltage-sensing domain (VSD). Inhibition is achieved by modifying channel gating (dark green arrows, gating modifiers) through binding with the extracellular linkers of the VSD (e.g., agatoxin) or with the activation gates of the pore (e.g., DHP). Another blocking mechanism includes the direct occlusion of the pore from the extracellular space (e.g., conotoxin). Small molecules are membrane permeable and can access the pore from the cytoplasm, thereby impeding the ion permeation (light green, pore blockers) (e.g., PAA). BTT-266 and BTT-369 disrupt the Ca_Vα₁–Ca_Vβ interaction interfering with channel trafficking. Gabapentin and pregabalin reduce channel membrane expression by binding with the Ca_Vα2δ subunit. BZT, benzothiazepine; DHP, dihydropyridine; PAA, phenylalkylamine.