Structural modifications in the distal, regulatory region of histamine H3 receptor antagonists leading to the identification of a potent anti-obesity agent

Szczepańska, Katarzyna; Pockes, Steffen; Podlewska, Sabina; Höring, Carina; Mika, Kamil; Latacz, Gniewomir; Bednarski, Marek; Siwek, Agata; Karcz, Tadeusz; Nagl, Martin; Bresinsky, Merlin; Mönnich, Denise; Seibel, Ulla; Kuder, Kamil; Kotańska, Magdalena; Stark, Holger; Elz, Sigurd; Kieć‐Kononowicz, Katarzyna

doi:10.1016/j.ejmech.2020.113041

Cited by 10 publications

(34 citation statements)

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“…It strongly prevented weight gain and reduced kcal intake in laboratory animals. It is noteworthy that KSK-94 also beneficially influenced some metabolic parameters by lowering plasma triglyceride and total cholesterol levels [12]. Of the two compounds tested in the present study, KSK-59 proved to be a more potent antagonist of the histamine H 3 receptor.…”

Section: Discussionmentioning

confidence: 58%

“…To exclude false-positive results, we also determined: (a) the influence of selected compounds on spontaneous activity, (b) whether the compounds cause stress, (c) whether they cause gastrointestinal disorders comparable to nausea, and d) whether inflammation might occur during chronic administration. Moreover, we discuss how these compounds differ from the others discovered in our laboratory so far [11,12]. In addition, in in vitro studies, we show that these compounds are antagonists of H 3 histamine receptor, and for the KSK-59 compound we also report the results of its membrane permeability.…”

Section: Introductionmentioning

confidence: 71%

“…In the presented model, experimental animals had continuous access to standard diet, which was additionally enriched with high-calorie products such as cheese, peanuts, chocolate or condensed milk. Such a model allows not only for the development of obesity and increase in the amount of fat in the peritoneum in the studied animals, but also for the development of certain metabolic disorders [11,12,18,19]. Already after the first week of the experiment, we noticed that animals from the control group that consumed palatable feed weighed significantly more than animals that consumed only standard feed.…”

Section: Discussionmentioning

confidence: 91%

“…In the preclinical studies it was found that histamine H 3 receptor antagonists reduce body weight. Several studies also showed that the blockade of histamine H 3 receptor significantly reduces food intake by animals [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…However, feeding is not in any way forced, as in other models where animals are fed only a high-fat diet, or when they are temporarily deprived of food (binge eating models). The experience related to this model suggests that greater differences (requiring less animals per group in order to obtain significant results) in the severity of disturbances in body weight and selected metabolic parameters are observed in female rats [ 25 , 26 , 27 ]. Therefore, to make the effect more noticeable, and in line with the principle of reducing the number of animals, female rats were selected.…”

Section: Introductionmentioning

confidence: 99%

Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating

et al. 2021

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GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.

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Improvement of Metabolic and Histological Changes of Adiposity in Rats by Synthetic Oleoyl Chalcones

Aly

Khathamy

Saad

et al. 2023

Chemistry & Biodiversity

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We previously reported that synthetic oleoyl chalcones had a favorable effect to alleviate metabolic consequences of obesity in male SD rats. In this work, we prepared and characterized by spectroscopic tools, a set of six oleoyl chalcones (5a -c, 10 and 11a,b). The comparative effects of the previously prepared oleoyl chalcones and their new synthetic analogs on metabolic and histological changes in obese male SD rats were studied. It was found that the oleoyl chalcones III a and IV were the best in improving many metabolic parameters, e. g., FBG, FI, ISI, TG, and total cholesterol. They cured systemic inflammation, through inhibition of the TNF-α and induction of adiponectin production. Moreover, chalcones III a and IV alleviated the oxidative stress accompanying obesity through the induction of the antioxidant enzymes GPX, SOD and CAT besides, GSH. Interestingly, chalcones III a and IV exerted hepatoprotective potency and ameliorated the manifestations of NAFLD via inhibition of apoptosis and induction of autophagy of hepatic cells. In conclusion, the oleoyl chalcones III a and IV were the most effective candidates among the series of synthetic chalcones in correcting body weight and the consequent metabolic and histological changes in adiposity.

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Structural modifications in the distal, regulatory region of histamine H3 receptor antagonists leading to the identification of a potent anti-obesity agent

Cited by 10 publications

References 50 publications

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

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

Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating

Improvement of Metabolic and Histological Changes of Adiposity in Rats by Synthetic Oleoyl Chalcones

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