ABSTRACT
The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.
Subject(s)
Drug Discovery , Factor IXa/antagonists & inhibitors , Factor Xa Inhibitors/pharmacology , Pyrimidines/pharmacology , Dose-Response Relationship, Drug , Factor IXa/metabolism , Factor Xa Inhibitors/chemical synthesis , Factor Xa Inhibitors/chemistry , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.
Subject(s)
Eating/drug effects , Energy Metabolism/drug effects , Nitriles/pharmacology , Obesity/physiopathology , Piperazines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Adipose Tissue/drug effects , Administration, Oral , Animals , Binding, Competitive , Body Weight/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Dietary Fats/administration & dosage , Dose-Response Relationship, Drug , Fatty Acids, Nonesterified/blood , Female , Galanin/genetics , Gene Expression/drug effects , Homeostasis/drug effects , Hypothalamic Hormones/genetics , Hypothalamus/drug effects , Hypothalamus/metabolism , Insulin/blood , Intracellular Signaling Peptides and Proteins/genetics , Iodine Radioisotopes , Leptin/blood , Male , Melanins/genetics , Mice , Mice, Inbred C57BL , Mice, Obese , Neuropeptide Y/genetics , Neuropeptides/genetics , Nitriles/administration & dosage , Obesity/etiology , Oligopeptides/metabolism , Orexin Receptors , Orexins , Piperazines/administration & dosage , Pituitary Hormones/genetics , Protein Binding , Receptors, G-Protein-Coupled , Receptors, Neuropeptide , Receptors, Somatostatin/genetics , Receptors, Somatostatin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Triglycerides/blood , Urea/administration & dosage , Urea/pharmacologyABSTRACT
OBJECTIVE: To identify and functionally characterize single-nucleotide polymorphisms (SNPs) in melanin-concentrating hormone (MCH)-R1 and -R2. RESEARCH METHODS AND PROCEDURES: The entire coding regions and intron/exon splice junction regions of MCH-R1 and MCH-R2 were sequenced from anonymous white (n=45) and African-American (n=46) individuals. DNA was analyzed, and SNPs were identified using Phred, Phrap, and Consed software. DNA constructs containing MCH-R1 and MCH-R2 SNPs were generated and expressed in CHO cells. The effect of the SNPs in MCH-R1 and MCH-R2 were assessed in receptor binding assays and functional assays measuring changes in intracellular cAMP and Ca2+ levels. RESULTS: We identified 12 SNPs in the MCH-R1 gene. Two of these SNPs are in coding regions, and one produces an arginine-for-glycine substitution at residue 34 in the MCH-R1 sequence. This SNP is present at a minor allele frequency of 15% in the African-American population tested in this study. We identified eight SNPs in the MCH-R2 gene. Four of these SNPs are in coding regions, and two produce amino acid substitutions. Lysine substitutes for arginine at residue 63 of the African-American population, and glutamine substitutes for arginine at residue 152 in whites (minor allele frequency of 2% for both SNPs). No changes in receptor binding or functional signaling were observed with the SNP mutations in MCH-R1 or MCH-R2. DISCUSSION: These data indicate that potential therapeutics designed to act at the MCH receptor are unlikely to have altered effects in subpopulations that express variant forms of MCH-R1 or MCH-R2.