Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: A novel recently identified potent MCH1 receptor antagonist, AZD1979, was studied in wild type and Mchr1 knockout (KO) mice and by using pair-feeding and indirect calorimetry in diet-induced obese (DIO) mice. The effect of AZD1979 on body weight was also studied in beagle dogs. KEY RESULTS:
AZD1979 bound to MCH1 receptors in the CNS and dose-dependently reduced body weight in DIO mice leading to improved homeostasis model assessment-index of insulin sensitivity. AZD1979 did not affect food intake or body weight in Mchr1 KO mice demonstrating specificity for the MCH1 receptor mechanism. In DIO mice, initial AZD1979-mediated body weight loss was driven by decreased food intake, but an additional component of preserved energy expenditure was apparent in pair-feeding and indirect calorimetry studies. AZD1979 also dose-dependently reduced body weight in dogs. CONCLUSION AND IMPLICATIONS:
AZD1979 is a novel potent MCH1 receptor antagonist that affects both food intake and energy expenditure. That AZD1979 also lowers body weight in a species expressing both MCH receptors holds promise for the use of MCH1 receptor antagonists for the treatment of human obesity.
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Authors | Karolina Ploj, Lambertus Benthem, Dorota Kakol-Palm, Peter Gennemark, Liselotte Andersson, Mikael Bjursell, Jenny Börjesson, Lillevi Kärrberg, Marianne Månsson, Madeleine Antonsson, Anders Johansson, Suzanne Iverson, Björn Carlsson, Andrew Turnbull, Daniel Lindén |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 173
Issue 18
Pg. 2739-51
(09 2016)
ISSN: 1476-5381 [Electronic] England |
PMID | 27400775
(Publication Type: Journal Article)
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Copyright | © 2016 The British Pharmacological Society. |
Chemical References |
- AZD1979
- Azetidines
- Mchr1 protein, mouse
- Oxadiazoles
- Receptors, Somatostatin
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Topics |
- Animals
- Azetidines
(administration & dosage, chemistry, pharmacology)
- Body Weight
(drug effects)
- Dogs
- Dose-Response Relationship, Drug
- Female
- Homeostasis
(drug effects)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Structure
- Oxadiazoles
(administration & dosage, chemistry, pharmacology)
- Receptors, Somatostatin
(antagonists & inhibitors, deficiency)
- Structure-Activity Relationship
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