LH 21

Description

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). 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. 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. 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. 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.

in vitro

previous study showed that lh-21 was able to inhibit the binding of [3h]cp55940 to cloned human and rat cb1 receptors with ic50 values of 631 ±98 nm, and 690 ± 41 nm, respectively. lh-21 acted as an inverse agonist in a camp functional assay using cultured cells expressing human, rat or mouse cb1 receptor. in addition, in cho cells overexpressing cb1, lh-21 was able to elevate camp, further confirming that lh-21 acted as an inverse agonist of cb1 in this model [1].

in vivo

animal study showed that when given acutely lh-21 could decrease food intake and enhance the anorectic actions of oleoylethanolamide, a feeding suppressant lipid acting on peripheral sensory terminals in a similar way as rimonabant. however, unlike rimonabant, chronic administration of lh-21 at 3 mg/kg was able to reduce feeding but did not improve hypercholesterolaemia or hypertriglyceridaemia; nor did it reduce liver fat deposits in zucker rats [2].

References

[1] 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. european journal of pharmacology 584, 338-342 (2008).
[2] 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. journal of neuroendocrinology 20, 116-123 (2008).