Focus Biomolecules

Resiniferatoxin (57444-62-9) is an ultrapotent TRPV1 activator (Ki=43 pM). ⁽¹⁾ Resiniferatoxin is 100-10,000 fold more potent than capsaicin for most responses yet displays a spectrum of activity distinct from capsaicin. ⁽²⁾ A potent sensory neuron excitotoxin. ⁽³⁾ Induces a long lasting analgesia in a rodent model of burn pain. ⁽⁴⁾ 

References

1) Szolcsanyi et al. (1990), Resiniferatoxin: an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons; J. Pharmacol. Exp. Ther., 255 923
2) Szallasi and Blumberg (1998), Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor; Life Sci. 47 1399
3) Winter et al. (1990) Cellular mechanism of action of resiniferatoxin: a potent sensory neuron excitotoxin; Brain Res. 520 131
4) Salas et al. (2017) Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury; Pain Med. 18 2453

YM-254890 (568580-02-9) is a novel Gαq/11 inhibitor. ⁽¹⁾ U46619-induced platelet aggregation is inhibited but phorbol ester- or ionophore-induced aggregation is not ⁽²⁾ (IC50 = 0.1-0.2 μM)1. It blocks Pasteurella multocida toxin-mediated activation of Gαq. ⁽³⁾ A highly useful new tool for studying Gαq/11-coupled receptor signaling and resulting cellular events. ⁽⁴⁾

References

1) Takasaki (2004), A novel Galphaq/11-selective inhibitor; J. Biol. Chem., 279 47438
2) Uemura et al. (2006), Biological properties of a specific Galpha q/11 inhibitor, YM-254890, on platelet functions and thrombus formation under high-shear stress; Br. J. Pharmacol., 148 61
3) Orth et al. (2005), Pasteurella multocida toxin-induced activation of RhoA is mediated via two families of G{alpha} proteins, G{alpha}g and G{alpha}12/13; J. Biol. Chem., 280 36701
4) Mizuno and Itoh (2009), Functions and regulatory mechanisms of Gq-signaling pathways; Neurosignals, 17 42

7-Cl-O-Nec1 (852391-15-2) is a necrostatin-1 (Cat.# 10-1162) analogue with superior potency (IC50 = 206nM vs 494nM), selectivity and metabolic stability in blocking RIP1. ^(1,2) 7-Cl-O-Nec1 shows no off-target inhibition of indolamine-2,3-deoxygenase (IDO) in contrast to Necrostatin-1 (Nec-1). ^(3,4) 7-Cl-O-Nec1 showed higher activity in inhibiting necroptosis in Jurkat cells than Necrostatin-1 (EC50 = 210 nM vs. EC50 = 490 nM), no non-specific cytotoxicity at high concentrations (100 μM) and reasonable pharmacokinetic characteristics when used in mice.2 7-Cl-O-Nec1 is recommended for cellular and in vivo use over Necrostatin-1. ⁽⁵⁾

References

1) Degterev et al. (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury; Nat. Chem. Biol., 1 112
2) Teng et al. (2005) Structure-activity relationship of novel necroptosis inhibitors; Bioorg. Med. Chem. Lett., 15 5039
3) Degterev et al. (2012) Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP1 kinase; Cell Death Differ., 20 366
4) Takahashi et al. (2012) Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models; Cell Death Dis., 3 e437
5) Degterev et al. (2013) Addendum: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury; Nat. Chem. Biol., 9 192