Dual-targeting approach on histamine H3 and sigma-1 receptor ligands as promising pharmacological tools in the treatment of CNS-linked disorders

2020 ◽  
Vol 27 ◽  
Author(s):  
Katarzyna Szczepańska ◽  
Kamil J. Kuder ◽  
Katarzyna Kieć-Kononowicz
Keyword(s):  
G Protein Coupled Receptors ◽  
Receptor Ligands ◽  
Receptor Antagonists ◽  
Histamine H3 Receptor ◽  
Sigma 1 Receptor ◽  
Biological Targets ◽  
H3 Receptor ◽  
Sigma 1 ◽  
G Protein Coupled ◽  
Histamine H3

: With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H3 receptor antagonists has clearly increased. Several combinations of different H3R pharmacophores with pharmacophoric elements of other G-protein coupled receptors, transporters or enzymes have been synthesized by numerous pharmaceutical companies and academic institutions. Since central nervous system disorders are characterized by diverse physiological dysfunctions and deregulations of a complex network of signaling pathways, optimal multipotent drugs should simultaneously and peculiary modulate selected groups of biological targets. Interestingly, very recent studies have shown that some of clinically evaluated histamine H3 receptor antagonists possess nanomolar affinity for sigma-1 receptor binding sites, suggesting that this property might play a role in their overall efficacy. The sigma-1 receptor, unusual and yet obscure protein, is supposed to be involved in numerous CNS pathologies through neuroprotection and neuroplasticity. These two different biological structures, histamine H3 and sigma-1 receptors, combined can represent potential fruitful target for therapeutic developments in tackling numerous human diseases.

Drug-receptor kinetics and sigma-1 receptor affinity differentiate clinically evaluated histamine H3 receptor antagonists

2019 ◽  
Vol 144 ◽  
pp. 244-255 ◽  
Author(s):  
Darren M. Riddy ◽  
Anna E. Cook ◽  
David M. Shackleford ◽  
Tracie L. Pierce ◽  
Elisabeth Mocaer ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Histamine H3 Receptor ◽  
Sigma 1 Receptor ◽  
Receptor Affinity ◽  
Receptor Kinetics ◽  
H3 Receptor ◽  
Sigma 1 ◽  
Drug Receptor ◽  
Histamine H3

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

2021 ◽  
Vol 14 (11) ◽  
pp. 1080
Author(s):  
Kamil Mika ◽  
Małgorzata Szafarz ◽  
Marek Bednarski ◽  
Gniewomir Latacz ◽  
Sylwia Sudoł ◽  
...  
Keyword(s):  
Weight Gain ◽  
Glucose Tolerance ◽  
Rat Model ◽  
Overweight And Obesity ◽  
Female Rats ◽  
Receptor Ligands ◽  
Receptor Antagonists ◽  
Histamine H3 Receptor ◽  
H3 Receptor ◽  
Histamine H3

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.

Diether (substituted) piperidine derivatives as novel, histamine H3 receptor ligands

2009 ◽  
Vol 58 (S1) ◽  
pp. 47-48
Author(s):  
K. J. Kuder ◽  
X. Ligneau ◽  
J.-C. Camelin ◽  
D. Łażewska ◽  
J.-C. Schwartz ◽  
...  
Keyword(s):  
Receptor Ligands ◽  
Histamine H3 Receptor ◽  
H3 Receptor ◽  
Histamine H3

ChemInform Abstract: 4-Chlorobenzyl Sulfonamide and Sulfamide Derivatives of Histamine Homologues: The Design of Potent Histamine H3 Receptor Antagonists.

ChemInform ◽  
2010 ◽  
Vol 31 (8) ◽  
pp. no-no
Author(s):  
Matthew J. Tozer ◽  
Ildiko M. Buck ◽  
Tracey Cooke ◽  
S. Barret Kalindjian ◽  
Iain M. McDonald ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Histamine H3 Receptor ◽  
H3 Receptor ◽  
Derivatives Of ◽  
Histamine H3

ChemInform Abstract: Substituted N-Phenylcarbamates as Histamine H3 Receptor Antagonists with Improved in vivo Potency.

ChemInform ◽  
2010 ◽  
Vol 31 (24) ◽  
pp. no-no
Author(s):  
S. Reidemeister ◽  
H. Stark ◽  
X. Ligneau ◽  
C. R. Ganellin ◽  
J.-C. Schwartz ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Histamine H3 Receptor ◽  
H3 Receptor ◽  
Histamine H3

scholarly journals The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors

2019 ◽  
Vol 63 (4) ◽  
pp. R81-R92 ◽  
Author(s):  
David Aguinaga ◽  
Mireia Casanovas ◽  
Rafael Rivas-Santisteban ◽  
Irene Reyes-Resina ◽  
Gemma Navarro ◽  
...  
Keyword(s):  
Eating Disorders ◽  
Drugs Of Abuse ◽  
Common Factor ◽  
G Protein Coupled Receptors ◽  
Sigma 1 Receptor ◽  
New Findings ◽  
Sigma 1 ◽  
Seeking Behavior ◽  
Food Seeking ◽  
G Protein Coupled

Addiction and eating disorders involve brain reward circuits. Binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after drug use is discontinued. Exciting new findings show that receptors for the ‘hunger’ hormone, ghrelin, directly interact with the sigma-1 receptor (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor as a general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders.

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