LH 21

LH 21 is a 1,2,4-triazole that acts as a cannabimimetic. It has a relatively low-affinity for the central cannabinoid (CB₁) receptor (K_i = 855 nM).¹ However, it interferes, at low nanomolar concentrations, with the action of the potent CB₁ agonist WIN 55,212-2 on murine vas deferens, suggesting that LH 21 acts as a silent CB₁ antagonist.¹ Consistent with this interpretation, LH 21 diminishes the in vivo effects of WIN 55,212-2 on standard CB tetrad responses in mice and reduces food intake and body weight gain in obese Zucker rats.^1,2,3 However, in CHO cells overexpressing CB₁, LH 21 is able to elevate cAMP, suggesting that, in this model, it acts as an inverse agonist of CB₁.⁴ Furthermore, LH 21 suppresses food intake and body weight gain in both wild-type and CB₁ receptor knockout mice, indicating that this receptor is not necessary for these effects.⁴

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1. Jagerovic, N., Hernandez-Folgado, L., Alkorta, I., et al. Discovery of 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif. J. Med. Chem. 47(11), 2939-2942 (2004).

2. Pavon, F.J., Bilbao, A., Hernández-Folgado, L., et al. Antiobesity effects of the novel neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole - LH 21. Neuropharmacology 51(2), 358-366 (2006).

3. Pavón, F.J., Serrano, A., Pérez-Valero, V., et al. Central versus peripheral antagonism of cannabinoid CB₁ receptor in obesity: Effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats. J. Neuroendocrinol. 20(Suppl 1), 116-123 (2008).

4. Chen, R.Z., Frassetto, A., Lao, J.Z., et al. Pharmacological evaluation of LH-12, a newly discovered molecule that binds to cannabinoid CB₁ receptor. Eur. J. Pharmacol. 584(2-3), 338-342 (2008).

Romero-Zerb, S.Y., Ruz-Maldonado, I., Espinosa-Jimenez, V., et al. The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice. Sci. Rep. 7(1), 3946 (2017).