Tetrodotoxin: History, Biology, and Synthesis

Abstract

This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018.

Human brain organoids assemble functionally integrated bilateral optic vesicles

“…In on-cell configuration, spontaneous action potentials could be measured, which were sometimes sensitive (Figure 6K) and occasionally resistant to Tetrodotoxin (TTX). TTX is a neurotoxin that selectively blocks sodium channels (Makarova et al, 2019). The resistance to TTX treatment is typical for retinal cells, which possess TTX-resistant voltage-gated sodium channels (O'Brien et al, 2008).…”

Fifteen years of NaV1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy?

“…That is, their efficacy depends on the gating state of the channel, with higher affinity for the open or inactivated state compared to the resting state (Ragsdale et al, 1994).However, the most well-studied small-molecule NaV channel blocker, tetrodotoxin (TTX),does not have a state-dependent mechanism of action. TTX is a guanidinium alkaloid derived from a variety of venomous and poisonous animals including pufferfish and the blue-ringed octopus (Makarova et al, 2019). TTX has been a vital pharmacological tool for assessing NaVchannel function, and indeed NaV channels are classified based on their sensitivity to the toxin: NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.6, and NaV1.7 are TTX-sensitive (TTX-S;low nM IC50) while Na-V1.5, NaV1.8, and NaV1.9 are TTX-resistant (TTX-R; low µM IC50TTX concentrations required for significant inhibition) (Catterall, 2000).…”

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

“…TTX has long been used in Chinese and Japanese traditional medicine. Pufferfish extracts were used for centuries to alleviate neuralgia in patients affected by leprosy, reduce tetanus-related muscle spasms, and relieve pain resulting from rheumatoid arthritis [31,32]. Today, modern pharmacological studies have supported the beneficial effects of TTX on pain [15,17,[33][34][35][36].…”