Zucapsaicin

Pharmacology

Zucapsaicin mediates an antinociceptive action via acting as an agonist at TRPV1. TRPV1 play an important physiological role of transducing chemical, mechanical and thermal stimuli as well as pain transduction, and participate in pain modulation and perception. They are mainly distributed in C sensory nerve fibers as well as Aẟ fibers to transmit sensory information involving inflammatory and neuropathic pain, and activation of these channels releases somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation [A19720]. Zucapsaicin is also reported to affect the peptidergic afferent neurons via a desensitization mechanism to decrease the levels of dorsal root ganglia and sciatic calcitonin gene-related peptide (CGRP) and substance P (SP) [L877].

Pharmacodynamics

Zucapsaicin mediates an antinociceptive action via acting as an agonist at TRPV1. TRPV1 play an important physiological role of transducing chemical, mechanical and thermal stimuli as well as pain transduction, and participate in pain modulation and perception. They are mainly distributed in C sensory nerve fibers as well as Aẟ fibers to transmit sensory information involving inflammatory and neuropathic pain, and activation of these channels releases somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation. Zucapsaicin is also reported to affect the peptidergic afferent neurons via a desensitization mechanism to decrease the levels of dorsal root ganglia and sciatic calcitonin gene-related peptide (CGRP) and substance P (SP).

Mechanism of action

Zucapsaicin excites and desensitizes C-fibers via agonist at TRPV1 on nociceptive neurons. It binds to intracellular sites and initially stimulates the channels, causing burning sensation. The mechanism of pharmacological action of zucapsaicin has not been fully understood yet. It is suggested that this compound, similarly to its trans isomer, is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker. Capsaicin is able to excite and desensitize C-fibers. As such, it is not only able to cause pain, but also exhibit analgesic properties. Initially, it stimulates TRPV1, which is responsible for a burning sensation. This effect is followed by a longlasting refractory state – ‘desensitization’ – during which the previously excited sensory neurons become unresponsive to capsaicin and other stimuli. It was shown that desensitization and tachyphylaxis of TRPV1 channels contribute to capsaicin-induced pain relief. Desensitization of TRPV1 represents the main mechanism of its inhibitory function.

Three distinct pathways of capsaicin-induced desensitization have been described: i) activation of calcineurin, which results in dephosphorylation of TRPV1; ii) activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate hydrolysis (rather controversial) and iii) activation of calcium-dependent protein kinase C isoforms and subsequent channel phosphorylation. Desensitization involves both tachyphylaxis (short-term desensitization) and long-term, persistent, desensitization. It is suggested that the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides are implicated in desensitization. The exhaustion of SP reserves renders neurons desensitized and refractory. These mechanisms of desensitization are not fully understood. It is thought that the short-term desensitization is related to capsaicin's ability to block the intra-axonal transport of NGF, SP and somatostatin.

The desensitization is a reversible phenomenon. It begins a few hours after capsaicin application and may last even several weeks. The reversible desensitization was found useful in the treatment of pain, whereas the site-specific ablation of sensory nerves transmitting pain stimuli is a promising approach (‘molecular scalpel’) to achieve a permanent pain relief in patients suffering from bone cancer pain or HIV-induced neuropathies. Desensitization and depletion of pronociceptive neurotransmitters induce chemical denervation with a loss of function, which is clinically used in osteoarthritis, diabetic neuropathy, psoriasis and others. In dorsal root ganglia and the sciatic nerve, zucapsaicin decreases levels of SP and CGRP, indicating that it influences peptidergic afferent neurons via a desensitization mechanism[41]. When administered topically, the intended targets for zucapsaicin are the neurons that innervate the local area of application. These neurons transmit pain toward the CNS.

Pharmacokinetics

Absorption

Zucapsaicin displays low systemic absorption and localizes at the area of application. In animal studies, systemic absorption is 0.075%.

Metabolism

In vitro studies demonstrates weak to moderate inhibitory effects on various cytochrome P450 enzymes, although not clinically significant due to low systemic absorption.

Route of elimination

In rat studies, zucapsaicin and its metabolites are slowly excreted into urine and feces (up to 2/3), with minimal elimination via exhalation following dermal administration.

Half life

In rats, the elimination half life of zucapsaicin and its metabolites is approximately 7 to 11 hours.

Toxicity

Most common adverse effects involved application site reactions such as transient burning and warm sensation. Other adverse effects observed in clinical trials are eye irritation, arthralgia, aggravated osteoarthritis, burning sensation, headache, cough and sneezing. Oral LD50 in mouse is 87.5 mg/kg in male and 90 mg/kg in males and 60 mg/kg in females.

Chemical and Physical Properties

Computed properties

References

References

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