Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating
Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H<sub>3</sub> receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and r...
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MDPI AG
2021
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oai:doaj.org-article:4a2cda7eb07b4e9996441514b99f7a6c2021-11-25T18:39:10ZHistamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating10.3390/ph141110801424-8247https://doaj.org/article/4a2cda7eb07b4e9996441514b99f7a6c2021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1080https://doaj.org/toc/1424-8247Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H<sub>3</sub> 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 H<sub>3</sub> 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 H<sub>3</sub> 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 H<sub>3</sub> 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.Kamil MikaMałgorzata SzafarzMarek BednarskiGniewomir LataczSylwia SudołJadwiga HandzlikKrzysztof PociechaJoanna KnutelskaNoemi NicosiaKatarzyna SzczepańskaKamil J. KuderKatarzyna Kieć-KononowiczMagdalena KotańskaMDPI AGarticleexcessive eating modelobesityhistamine H<sub>3</sub> receptor ligands(4-pyridyl)piperazine derivativesMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1080, p 1080 (2021) |
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excessive eating model obesity histamine H<sub>3</sub> receptor ligands (4-pyridyl)piperazine derivatives Medicine R Pharmacy and materia medica RS1-441 |
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excessive eating model obesity histamine H<sub>3</sub> receptor ligands (4-pyridyl)piperazine derivatives Medicine R Pharmacy and materia medica RS1-441 Kamil Mika Małgorzata Szafarz Marek Bednarski Gniewomir Latacz Sylwia Sudoł Jadwiga Handzlik Krzysztof Pociecha Joanna Knutelska Noemi Nicosia Katarzyna Szczepańska Kamil J. Kuder Katarzyna Kieć-Kononowicz Magdalena Kotańska Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating |
| description |
Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H<sub>3</sub> 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 H<sub>3</sub> 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 H<sub>3</sub> 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 H<sub>3</sub> 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. |
| format |
article |
| author |
Kamil Mika Małgorzata Szafarz Marek Bednarski Gniewomir Latacz Sylwia Sudoł Jadwiga Handzlik Krzysztof Pociecha Joanna Knutelska Noemi Nicosia Katarzyna Szczepańska Kamil J. Kuder Katarzyna Kieć-Kononowicz Magdalena Kotańska |
| author_facet |
Kamil Mika Małgorzata Szafarz Marek Bednarski Gniewomir Latacz Sylwia Sudoł Jadwiga Handzlik Krzysztof Pociecha Joanna Knutelska Noemi Nicosia Katarzyna Szczepańska Kamil J. Kuder Katarzyna Kieć-Kononowicz Magdalena Kotańska |
| author_sort |
Kamil Mika |
| title |
Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating |
| title_short |
Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating |
| title_full |
Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating |
| title_fullStr |
Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating |
| title_full_unstemmed |
Histamine H<sub>3</sub> Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating |
| title_sort |
histamine h<sub>3</sub> receptor ligands—ksk-59 and ksk-73—reduce body weight gain in a rat model of excessive eating |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/4a2cda7eb07b4e9996441514b99f7a6c |
| work_keys_str_mv |
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