KSK-74: Dual Histamine H3 and Sigma-2 Receptor Ligand with Anti-Obesity Potential

Abstract

Many studies involving compounds that enhance histamine release, such as histamine H3 receptor (H3R) antagonists, have shown efficacy in inhibiting weight gain, but none have passed clinical trials. As part of the search for H3 receptor ligands that have additional properties, the aim of this study is to evaluate the activity in the reduction in weight gain in a rat model of excessive eating, as well as the impact on selected metabolic parameters, and the number and size of adipocytes of two new H3R antagonists, KSK-60 and KSK-74, which also exert a significant affinity at the sigma-2 receptor. Compounds KSK-60 and KSK-74 are homologues and the elongation of the distal part of the molecule resulted in an approximate two-fold reduction in affinity at H3R, but simultaneously an almost two-fold increase in affinity at the sigma-2 receptor. Animals fed palatable feed and receiving KSK-60 or KSK-74 both at 10 mg/kg b.w. gained significantly less weight than animals in the control obese group. Moreover, KSK-74 significantly compensated for metabolic disturbances that accompany obesity, such as an increase in plasma triglyceride, resistin, and leptin levels; improved glucose tolerance; and protected experimental animals against adipocyte hypertrophy. Furthermore, KSK-74 inhibited the development of inflammation in obesity-exposed adipose tissue. The in vivo pharmacological activity of the tested ligands appears to correlate with the affinity at the sigma-2 receptors; however, the explanation of this phenomenon requires further and extended research.

Evaluation of Some Safety Parameters of Dual Histamine H3 and Sigma-2 Receptor Ligands with Anti-Obesity Potential

“…In our previous studies on the effect of tested ligands on body weight in a model of excessive eating in rats, we showed that spontaneous activity—measured by long-term motility monitoring in home cage conditions—is not significantly affected by any of these ligands when administered once and chronically i.p. at a dose of 10 mg/kg/day [ 21 , 22 , 23 , 24 ]. Additional studies are required to indicate the exact mechanism underlying this effect.…”

“…The study evaluating the activities of alanine aminotransferase (AlaT), aspartate aminotransferase (AspaT), gamma-glutamyl transpeptidases (gGT), and alkaline phosphatase (ALP) was carried out after completing the excessive eating model experiments described in our previous work [ 21 , 22 , 23 ]. Compounds were administered for twenty-eight days at a dose of 10 mg/kg b.w./day.…”

“…In our previous work, we focused primarily on evaluating the efficacy of the tested compounds in the animal model of excessive eating and determining their effects on selected metabolic parameters [ 21 , 22 , 23 , 24 ]. The present study focusses primarily on determining the safety (impact on the central nervous system and cardiovascular system) of some of the most active dual ligands of the histamine H 3 receptor and the sigma-2 receptors.…”

“…The present study focusses primarily on determining the safety (impact on the central nervous system and cardiovascular system) of some of the most active dual ligands of the histamine H 3 receptor and the sigma-2 receptors. Recent studies have shown that some evaluated histamine H 3 receptor antagonists possess a nanomolar affinity for sigma-2 receptor binding sites, suggesting that this property might play a role in their overall efficacy and side effects [ 23 , 25 ]. Pitolisant, a drug used in narcolepsy, is a good example of a ligand for both the histamine H 3 and sigma-2 receptors.…”

Phenylpiracetam: molecular mechanisms of effects in obesity

“…Хемореактомный анализ показал возможность того, что фонтурацетам -наиболее активный ингибитор H3R (IC50 = 55 нМ). Соединения, которые усиливают высвобождение гистамина (такие как селективные антагонисты H3R), исследуются как средства для лечения ожирения [43].…”