Histamine H3 Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating

Abstract

Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H3 receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and release and affect a number of other neurotransmitters (norepinephrine, acetylcholine, γ-aminobutyric acid, serotonin, substance P) thus influencing the food intake. Based on the preliminary studies determining affinity, intrinsic activity, and selected pharmacokinetic parameters, two histamine H3 receptor ligands were selected. Female rats were fed palatable food for 28 days and simultaneously administered the tested compounds intraperitoneally (i.p.) at a dose of 10 or 1 mg/kg b.w./day. Weight was evaluated daily and calorie intake was evaluated once per week. The plasma levels of cholesterol, triglycerides, leptin, adiponectin, ghrelin, corticosterone, CRP and IL-6 were determined at the end of experiment. The glucose tolerance test was also performed. To exclude false positives, the effect of tested compounds on spontaneous activity was monitored during the treatment, as well as the amount of consumed kaolin clay was studied as a reflection of possible gastrointestinal disturbances comparable to nausea. The histamine H3 receptor antagonists KSK-59 and KSK-73 administered i.p. at a dose of 10 mg/kg b.w. prevented weight gain in a rat model of excessive eating. They reduced adipose tissue deposits and improved glucose tolerance. Both compounds showed satisfying ability to penetrate through biological membranes determined in in vitro studies. Compound KSK-73 also reduced the caloric intake of the experimental animals what indicates its anorectic effect. These results show the pharmacological properties of histamine H3 receptor antagonists, (4-pyridyl)piperazine derivatives, as the compounds causing not only slower weight gain but also ameliorating some metabolic disorders in rats having the opportunity to overeat.

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

“…In our previous work, we published the results for their structural analogues, compounds KSK-59 and KSK-73, which differ only in the distal part of the molecules (acetyl versus propionyl derivatives, Figure 1) [22]. It should be noted that compound KSK-73 prevented weight gain and metabolic disturbances more than compound KSK-59, which is partially consistent with our current results, in which KSK-74 is also more effective than KSK-60.…”

“…Since treated rats consumed a similar amount of calories to the control rats fed palatable feed, we speculated that, other than a reduction in caloric intake, mechanisms resulting in the lower weight gain in these animals are involved. We obtained similar results earlier when testing other ligands from this group of compounds, namely, not all of them decreased the amount of calories consumed [21,22]. We reported that i.p.…”

“…The effect of H 3 receptor antagonists on food intake has already been described in the literature [20][21][22]29]. Since treated rats consumed a similar amount of calories to the control rats fed palatable feed, we speculated that, other than a reduction in caloric intake, mechanisms resulting in the lower weight gain in these animals are involved.…”

“…Furthermore, the pharmacokinetic properties of compounds KSK-73 and KSK-74 are more favorable compared to their homologues KSK-59 and KSK-60. In particular, they have a much larger volume of distribution, which could indicate their better ability to freely cross biological membranes and distribute throughout the body [22]. Additionally, according to Lipinski's "Rule of Five" (molecular weight ≤ 500; LogP ≤ 5; hydrogen-bond donors ≤ 5; hydrogen-bond acceptors ≤ 10; number of rotatable bonds ≤ 10), compounds KSK-60 and KSK-74 are likely to have good absorption and permeability.…”

“…Considering its promising anti-obesity properties, our research group chose the KSK19 lead structure as a reference to develop new selective H3R ligands. Our recent study demonstrated high efficacy in inhibiting weight gain in a model of excessive eating and favorable pharmacokinetic properties for four of the ligands tested: KSK-61 and KSK-63, KSK-59 and KSK-73 [21,22]. Based on our recent work, we included two new histamine H3R antagonists in our study, KSK-60 and KSK-74 (Figure 1) [12], which are structural analogs of compounds KSK-59 and KSK-73.…”