ABSTRACT
A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.
Subject(s)
Anti-Obesity Agents/chemistry , Receptors, Ghrelin/agonists , Administration, Oral , Animals , Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/pharmacokinetics , Disease Models, Animal , Drug Inverse Agonism , Half-Life , Humans , Male , Mice , Mice, Inbred ICR , Microsomes, Liver/metabolism , Niacinamide/administration & dosage , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Obesity/drug therapy , Obesity/pathology , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/metabolism , Structure-Activity RelationshipABSTRACT
New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.
Subject(s)
Niacinamide/analogs & derivatives , Receptors, Ghrelin/agonists , Receptors, Ghrelin/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Appetite Regulation/drug effects , Drug Design , HEK293 Cells , High-Throughput Screening Assays , Humans , Mice , Niacinamide/chemistry , Niacinamide/pharmacology , Obesity/drug therapy , Obesity/physiopathology , Rats , Structure-Activity RelationshipABSTRACT
Pathophysiological features of chronic obstructive pulmonary disease (COPD) include systemic abnormalities, such as weight loss and skeletal muscle wasting. Although cigarette smoke (CS) is a major risk factor in COPD, the systemic effects of CS exposure remain to be elucidated. In this study, rats were exposed to CS or smoke-free air for 12 weeks. CS-exposed rats developed emphysema and had significantly lower body weight and food intake than control rats. The plasma ghrelin levels significantly increased with an upregulation of gastric ghrelin mRNA expression induced by CS exposure. Further, we observed low plasma insulin-like growth factor-1 levels and high tumor necrosis factor-α levels. A significant reduction of skeletal muscle strength and an increase in the mRNA expression of catabolic factors was observed in CS-exposed rats. These results indicated that chronic CS exposure induced not only pulmonary emphysema but also systemic abnormalities related to muscle catabolism associated with inflammatory responses.
Subject(s)
Emphysema/chemically induced , Muscle, Skeletal/drug effects , Nicotiana/adverse effects , Smoke/adverse effects , Animals , Body Weight/drug effects , Cytokines/blood , Eating/drug effects , Emphysema/blood , Emphysema/metabolism , Gastric Mucosa/metabolism , Ghrelin/blood , Ghrelin/genetics , Lung/drug effects , Male , Muscle Proteins/genetics , Muscle Weakness/chemically induced , Muscle, Skeletal/metabolism , Myostatin/genetics , RNA, Messenger/metabolism , Rats, Wistar , SKP Cullin F-Box Protein Ligases/genetics , Stomach/drug effects , Tripartite Motif Proteins , Ubiquitin-Protein Ligases/geneticsABSTRACT
Cigarette smoking, which is a well-known major risk factor for chronic obstructive pulmonary disease (COPD), causes both pulmonary and extrapulmonary abnormalities. Ghrelin is a gastric peptide that regulates energy homeostasis. In the present study, we investigated the effects of ghrelin on the catabolic changes, respiratory function and emphysema in an animal model of COPD induced by chronic exposure to cigarette smoke. Rats were exposed to cigarette smoke, and they were administered human ghrelin (0.1 or 1 mg/kg, subcutaneous, twice daily) for 12 weeks. Compared with air-exposed rats, body weight gain, food intake, food efficiency, tidal volume, peak expiratory flow rate, and forced expiratory volume at 100 ms were significantly lower, while functional residual capacity, lung capacity, and neutrophils in bronchoalveolar lavage fluid were significantly higher in cigarette smoke-exposed rats. These indicated that the systemic abnormalities associated with COPD developed after the exposure to cigarette smoke. Ghrelin significantly and dose-dependently increased the body weight gain and food efficiency in cigarette smoke-exposed rats. In ghrelin-treated rats, skeletal muscle strength, which tended to be lowered by cigarette smoke exposure, was improved. Ghrelin ameliorated respiratory function and emphysema in a dose-dependent manner, but did not inhibit the increase in neutrophils in the bronchoalveolar lavage fluid. The respiratory functional parameters and lung capacity were significantly correlated with body weight gain. These results suggest that ghrelin inhibited the development of the catabolic changes, respiratory dysfunction, and emphysema that were induced by cigarette smoke exposure in rats, at least in part, through the amelioration of nutritional status.
