title: Effects of a novel potent melanin-concentrating hormone receptor 1 antagonist, AZD1979, on body weight homeostasis in mice and dogs.
abstract: Melanin-concentrating hormone (MCH) is an orexigen, and while rodents express one MCH receptor (MCH1 receptor), humans, non-human primates and dogs express two MCH receptors (MCH1 and MCH2 ). MCH1 receptor antagonists have been developed for the treatment of obesity and lower body weight in rodents. However, the mechanisms for the body weight loss and whether MCH1 receptor antagonism can lower body weight in species expressing both MCH receptors are not fully understood.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.|Drug Safety & Metabolism, AstraZeneca Mölndal, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ploj
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Benthem
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kakol-Palm
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Gennemark
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.|Drug Safety & Metabolism, AstraZeneca Mölndal, Sweden.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Discovery Sciences Transgenics, AstraZeneca, Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Bjursell
authors.affiliation: Discovery Sciences Transgenics, AstraZeneca, Mölndal, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Börjesson
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.|Drug Safety & Metabolism, AstraZeneca Mölndal, Sweden.
authors.forename: Lillevi
authors.initials: L
authors.lastname: Kärrberg
authors.affiliation: Discovery Sciences Statistics, AstraZeneca Mölndal, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Månsson
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Antonsson
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Johansson
authors.affiliation: Drug Safety & Metabolism, AstraZeneca Mölndal, Sweden.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Iverson
authors.affiliation: Early Clinical Development, AstraZeneca, Mölndal, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Andrew
authors.initials: A
authors.lastname: Turnbull
authors.affiliation: Cardiovascular & Metabolic Diseases innovative Medicines (CVMD iMed), AstraZeneca Mölndal, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindén
mesh_terms: D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D010069:Oxadiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000172:deficiency; D013329:Structure-Activity Relationship
chemical_list: C000609913:AZD1979; D001384:Azetidines; C491209:Mchr1 protein, mouse; D010069:Oxadiazoles; D017481:Receptors, Somatostatin