ABSTRACT
The main purpose of this study was to examine the effects of a selective histamine H(3) receptor antagonist, NNC 38-1202, on caloric intake in pigs and in rhesus monkeys. The compound was given intragastrically (5 or 15 mg/kg), to normal pigs (n=7) and subcutaneously (1 or 0.1mg/kg) to obese rhesus monkeys (n=9). The energy intake recorded following administration of vehicle to the same animals served as control for the effect of the compound. In addition, rhesus monkey and pig histamine H(3) receptors were cloned from hypothalamic tissues and expressed in mammalian cell lines. The in vitro antagonist potencies of NNC 38-1202 at the H(3) receptors were determined using a functional GTPgammaS binding assay. Porcine and human H(3) receptors were found to have 93.3% identity at the amino acid level and the close homology between the monkey and human H(3) receptors (98.4% identity) was confirmed. The antagonist potencies of NNC 38-1202 at the porcine, monkey and human histamine H(3) receptors were high as evidenced by K(i)-values being clearly below 20 nM, whereas the K(i)-value on the rat H(3) receptor was significantly higher (56+/-6.0 nM). NNC 38-1202, given to pigs in a dose of 15 mg/kg, produced a significant (p<0.05) reduction (55%) of calorie intake compared with vehicle alone, (132.6+/-10.0 kcal/kgday versus 59.7+/-10.2 kcal/kgday). In rhesus monkeys administration of 0.1 and 1mg/kg decreased (p<0.05) average calorie intakes by 40 and 75%, respectively. In conclusion, the present study demonstrates that antagonistic targeting of the histamine H(3) receptor decreases caloric intake in higher mammalian species.
Subject(s)
Energy Intake/drug effects , Histamine Antagonists/pharmacology , Receptors, Histamine H3/physiology , Animals , Energy Intake/physiology , Humans , Macaca mulatta , Rats , Sus scrofaABSTRACT
OBJECTIVE: The purpose of the present study was to examine the metabolic effects of a specific histamine H(3) receptor antagonist, the cinnamic amide NNC 0038-0000-1202 (NNC 38-1202). RESEARCH METHODS AND PROCEDURES: Effects of NNC 38-1202 on paraventricular levels of histamine and acute effects on food intake were followed in normal rats, whereas effects on body weight homeostasis and lipid metabolism were studied in a rat model of diet-induced obesity (DIO). RESULTS: NNC 38-1202, administered as single oral doses of 15 and 30 mg/kg, significantly (p < 0.01) increased paraventricular histamine by 339 +/- 54% and 403 +/- 105%, respectively, compared with basal levels. The same doses produced significant (p < 0.01) reductions in food intake. In DIO rats receiving NNC 38-1202 in a daily dose of 5 mg/kg for 22 days, a decrease in food intake was associated with a significant (p < 0.001) net loss of body weight (-11.0 +/- 4.8 grams), compared with rats receiving vehicle, which gained 13.6 +/- 3.0 grams. Also, NNC 38-1202 significantly (p < 0.05) reduced plasma triglycerides by approximately 42%, in parallel with increases in plasma free fatty acids and beta-hydroxybutyrate levels. Despite reductions in food intake and body weight following administration of NNC 38-1202, no sign of a decrease in energy expenditure was observed, and whole-body lipid oxidation was significantly (p < 0.05) increased in the period after dosing. DISCUSSION: The present study suggests that antagonistic targeting of the histamine H(3) receptor decreases food intake, body weight, and plasma TG levels and, thus, represents an interesting approach to treatment of obesity and associated hyperlipidemia.
Subject(s)
Eating/drug effects , Histamine Antagonists/pharmacology , Histamine/metabolism , Obesity/drug therapy , Paraventricular Hypothalamic Nucleus/metabolism , Receptors, Histamine H3/drug effects , Triglycerides/blood , Administration, Oral , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Histamine Antagonists/administration & dosage , Male , Obesity/blood , Obesity/metabolism , Piperazines/administration & dosage , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Weight LossABSTRACT
A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition.
Subject(s)
Cinnamates/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/drug effects , Thiazines/pharmacology , Urea/analogs & derivatives , Urea/chemistry , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Histamine Antagonists/chemical synthesis , Histamine Antagonists/chemistry , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/chemistry , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
Benzo[b]thiophene-2-carboxamides and benzo[b]furan-2-carboxamides have been found to be antagonists on the human histamine-3-receptor, showing a Ki value of as low as 4 nM.
Subject(s)
Amides/chemistry , Amides/pharmacology , Furans/chemistry , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Thiophenes/chemistry , Amides/chemical synthesis , Benzene/chemistry , Histamine Antagonists/chemistry , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
With the aim of identifying structurally novel, centrally acting histamine H(3) antagonists, a series of 2-(4-alkylpiperazin-1-yl)quinolines was prepared. Systematic variation of the substituents led to highly potent histamine H(3) antagonists with low polar surface area and appropriate log P for blood-brain barrier penetration.
Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/drug effects , Animals , Biochemistry/methods , Blood-Brain Barrier/drug effects , Drug Evaluation, Preclinical/methods , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Quinolines/chemistry , Quinolines/pharmacology , Rats , Receptors, Histamine H3/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
With the aim of identifying structurally novel, centrally acting histamine H(3) antagonists, arrays of monoacyldiamines were screened. This led to the discovery of a series of 1-alkyl-4-acylpiperazines which were potent antagonists at the human histamine H(3) receptor. The most potent amides had antagonist potencies in the subnanomolar range.
Subject(s)
Histamine Antagonists/chemical synthesis , Piperazines/chemical synthesis , Receptors, Histamine H3/drug effects , Animals , CHO Cells , Cricetinae , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Humans , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Structure-Activity RelationshipABSTRACT
New imidazole-free H3 antagonists have been found in a series of cinnamic amides of (S)-(aminomethyl)pyrrolidines. The influence of the substituent on the aromatic moiety on the potency and the inhibition of three cytochrome P450 subtypes are also described.
Subject(s)
Amides/chemistry , Cinnamates/chemistry , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Pyrrolidines/chemistry , Amides/pharmacology , Animals , CHO Cells , Cinnamates/pharmacology , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme Inhibitors , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Histamine Antagonists/chemical synthesis , Molecular Structure , Pyrrolidines/pharmacologyABSTRACT
Human and rat histamine H(3) receptors were recombinantly expressed and characterized using receptor binding and a functional cAMP assay. Seven of nine agonists had similar affinities and potencies at the rat and human histamine H(3) receptor. S-alpha-methylhistamine had a significantly higher affinity and potency at the human than rat receptor, and for 4-[(1R*,2R*)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole (Perceptin) the preference was the reverse. Only two of six antagonists had similar affinities and potencies at the human and the rat histamine H(3) receptor. Ciproxifan, thioperamide and (1R*,2R*)-trans-2-imidazol-4 ylcyclopropyl) (cyclohexylmethoxy) carboxamide (GT2394) had significantly higher affinities and potencies at the rat than at the human histamine H(3) receptor, while for N-(4-chlorobenzyl)-N-(7-pyrrolodin-1-ylheptyl)guanidine (JB98064) the preference was the reverse. All antagonists also showed potent inverse agonism properties. Iodoproxyfan, Perceptin, proxyfan and GR175737, compounds previously described as histamine H(3) receptor antagonists, acted as full or partial agonists at both the rat and the human histamine H(3) receptor.
