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 (Ki = 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.
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].
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].
631 ±98 and 690 ± 41 nm for human and rat cb1 receptors, respectively
[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).
