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.