Novel Analgesics Targeting TRPV1 an Insight into the Mechanism

Abstract

Abstract

The strategies for the development of new analgesic drugs enable the semi-conduction of the propagation of action potential in nerves targeting neurotransmitters or synapsis. An alternative strategy could be the interaction and inactivation of the receptors for chronic pain and inflammation. Transient Receptor Potential Channels (TRPV) are a family of conserved integral membrane ion channels that mediate the transmembrane cationic flux down. The changes in the electrochemical gradient result in an increase in intracellular calcium and sodium ion concentration which plays an important role in depolarization cells propagation of neural action potential and muscle contraction. The role of nociceptive signals due to chemical stimuli needs to be made more effective. In search of a more effective molecule, we selected 20 capsaicin derivatives which included both known molecules and newly designed molecules. Molecules were selected considering their drug-likeness. The improved efficacy of a novel capsaicin derivative MS-3 ((IUPAC name: (6E) ‐N'‐(4‐hydroxy‐3‐methoxyphenyl) ‐8‐methylnon‐6‐ enehydrazide)) is reported in this work. MS-3 was compared against capsaicin and already marketed drugs zucapsaicin and nonivamide and improved binding was registered. In addition, evidence was obtained for drug-likeness and was better than others in most of the attributes of ADMET.

Transient receptor potential channels (TRP channels) are a family of evolutionary conserved integral membrane ion channels found in a variety of animal cells ranging from worms [1], fruit flies [2], and zebrafish [3] to mice and humans [4]. TRP channels were first discovered in the fly eye, where light-activated rhodopsin stimulates phospholipase C (PLC) to hydrolyse the minor plasma membrane lipid, phosphatidyl-inositol bisphosphate (PIP2) [5-10]. This, in turn, promotes the gating of TRP channels to depolarize the photoreceptor cell. TRP channels mediate the transmembrane flux of cations down their electrochemical gradients, thereby raising intracellular Ca²⁺ and Na⁺ concentrations and depolarizing the cell. Changes in transmembrane voltage (Vm) underlie neuronal action potential propagation and muscle contraction [5]. Voltage also plays a crucial role in non-excitable cells both by directing the driving force for calcium entry through plasma membrane channels and by controlling the gating of voltage-dependent Ca²⁺, K⁺, and Cl⁻ channels. Calcium entry through plasma membrane channels is recognized as a cellular signalling event per se: Effector proteins sensitive to elevated Ca²⁺ ion control a plethora of cellular events from transcriptional regulation to migration and proliferation [9].

Structurally TRPV1 is made up of four identical subunits and each subunit has an N-terminus and transmembrane region and a C-terminus region as shown in Figure 1 [10]. The N-terminus region consists of six ankyrin repeats forming six A helix connected by finger loops. The transmembrane region comprises 6 helical segments (S1–S6) where S1–S4 makes the voltage-sensing domain, and S5–S6 contributes to the pore formation. S1-S4 are connected to S5-S6 by a small linker segment and act as a foundation that allows the linker segment to move and contribute towards pore opening and activation of TRPV1. The transmembrane region also contains binding sites for capsaicin. The C-terminus consists of a TRP Domain (TRP-D) which interacts with pre-S1 suggesting some structural significance. Following this, are several Protein Kinase A (PKA) and Protein Kinase C (PKC) phosphorylation sites, and sites for binding calmodulin and phosphatidylinositol-4,5-bisphosphate (PIP2).

Transient Receptor Potential Channel 1 (TRPV1) is one of the most extensively studied members of the TRP family. It is a non-specific cation channel expression in various tissues throughout the body, which include the soma of Dorsal Root Ganglia (DRG) and nodose ganglia in the peripheral nervous system, non-neuronal cells like mast cells, glial cells, keratinocytes as well as in various regions of the brain. These are transducers of heat (> 42 ^oC) or chemical stimuli like vanilloid compounds (Ex. capsaicin) [8]. Once activated, TRPV1 allows the entry of monovalent and divalent cations like Na⁺, Mg^2+, and Ca²⁺ [9]. Initial activation causes a burning sensation followed by a long-lasting refractory state when the neurons are desensitized during which the neurons are unresponsive to other stimuli [10]. Here we will be discussing a novel capsaicin derivative that can serve as a potential therapeutic agent for the management of chronic and neuropathic pain.