3-(1<i>H</i>-Indazol-3-ylmethyl)-1,5-benzodiazepines:  CCK-A Agonists That Demonstrate Oral Activity as Satiety Agents

Henke, Brad R.; Willson, Timothy M.; Sugg, Elizabeth E.; Croom, Dallas K.; Dougherty, R. W.; Queen, Kennedy L.; Birkemo, Larry S.; Ervin, Gregory N.; Grizzle, Mary K.; Johnson, Michael F.; James, M K

doi:10.1021/jm960249k

Cited by 29 publications

(16 citation statements)

References 19 publications

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“…Peptide analogues of CCK provide one avenue for drug development (Moran et al 1992;Johnson et al 1994). The recently described benzodiazepines, which are CCK agonists, are a second way to use this strategy (Henke et al 1996). Antagonists to proteolytic degradation of CCK and CCK-releasing factors in the gastrointestinal tract are a third approach to enhancing the effect of CCK and to altering gastric emptying, gastric distention and food intake (Liddle, 1995).…”

Section: Cholecystokininmentioning

confidence: 99%

Afferent signals regulating food intake

2000

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Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. β-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

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Section: Cholecystokininmentioning

confidence: 99%

Afferent signals regulating food intake

2000

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“…21,22 Since the discovery of two subtypes of CCK receptors, CCK A receptors predominantly located in the periphery and the CCK B receptor located in the CNS, 23 numerous nonpeptidergic CCK A agonists have been synthesized and have been shown to mimic all properties of CCK. [24][25][26] We therefore tested whether HMR1426 was acting as a CCK A agonist. The CCK A agonist GW5824 inhibited cumulative milk consumption in mice after 2, 4 and 6 h on an average by 98%.…”

Section: Discussionmentioning

confidence: 99%

“…This makes it unlikely that HMR1426 effects energy expenditure, which was confirmed by direct measurements of energy expenditure after treatment with HMR1426 in rats. 24 …”

Section: Discussionmentioning

confidence: 99%

Analysis of the anorectic efficacy of HMR1426 in rodents and its effects on gastric emptying in rats

Bickel¹,

Gossel²,

Geisen³

et al. 2003

Int J Obes

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OBJECTIVES: Pharmacodynamics of HMR1426 in rodents. SUBJECTS: Male and female rats and male mice. MEASUREMENTS: 24 h feed consumption was measured. From the time curves IC 50 values of HMR1426 were calculated. Microanalysis of feeding behavior was determined. Macronutrient preference was measured, by offering rats three different diets. Gastric emptying was measured after liquid gastric loads or solid meals. In rats with gastric cannulas, milk consumption was measured with closed or open cannulas. Diabetes-related parameters and thyroid hormones were measured. RESULTS: HMR1426 inhibited feed consumption dose-dependently in rodents. Microstructural analysis of feeding after HMR1426 differed from central acting anorectics. HMR1426 inhibited consumption of fat-and carbohydrate-enriched diets. Gastric empyting was dose-and time-dependently delayed. Gastric emptying correlated with the time course of the anorectic effect. In sham-fed rats, HMR1426 had no anorectic effect with open cannulas. Anorectic effect occurred with closed cannulas. We proved that HMR1426 is not a CCK A agonist. CONCLUSION: The correlation between anorectic properties of HMR1426 and gastric emptying suggests that gastric emptying may cause the anorectic properties of HMR1426. The differences in microstructural feeding behavior between HMR1426 and centrally active anorectics makes it unlikely that HMR1426 acts via the CNS. Evidence for a peripheral mode of action is derived from sham-fed rats with open gastric fistula. When the milk fed was drained, HMR1426 was ineffective. HMR1426 is not a CCK A agonist. The molecular action of HMR1426 causing gastric emptying and its anorectic properties are under investigation.

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“…Continued investigation of the 1,5-benzodiazepine series replaced the C-3 phenyl of 80 with an indazolylmethyl group leading to GW-5823 (81, Fig. 24) [221], an orally active moderately selective CCK-A agonist (50-fold) over CCK-B. Unfortunately this compound showed poor bioavailability in rats due to delayed gastric emptying and rapid metabolism [222].…”

Section: 1glucagon-like Peptide-1 (Glp-1) Receptor Agonistsmentioning

confidence: 99%

Antiobesity Therapy: Emerging Drugs and Targets

Das

Chakrabarti²

2006

CMC

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Obesity and its associated morbidities and mortalities are the effects of imbalance between energy intake and expenditure. The healthcare burden for the treatment of obesity is significantly high, due to increased risk of secondary chronic diseases such as hypertension and associated co-morbidities such as diabetes and cardiovascular disease. Lack of physical activity, high fat diets and sedentary life styles are major factors contributing to obesity. However, genetic predisposition and ethnicity are increasingly found to cause obesity. Till date, approved therapeutics have addressed excess energy intake by acting on central neural circuits that regulate feeding or on peripheral mechanisms to reduce nutrient absorption from the gut. These approaches have met with moderate success; and recently with safety concerns, leaving an unmet medical need for effective and safe pharmacotherapy for obesity thereby posing a significant challenge to pharmaceutical industry. Potential antiobesity drugs, which are being investigated by different companies, can be classified in 4 broad categories: 1) Agents that primarily decrease appetite through central action; 2) Agents that primarily increase metabolic rate or affect metabolism through peripheral action; 3) Agents that act on gastrointestinal tract; and 4) Agents that not only affect obesity but also overall Metabolic Syndrome. The current review will deal mainly with different molecules, which are under development for the above-mentioned targets and also their potential benefits and disadvantages.

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3-(1H-Indazol-3-ylmethyl)-1,5-benzodiazepines: CCK-A Agonists That Demonstrate Oral Activity as Satiety Agents

Cited by 29 publications

References 19 publications

Afferent signals regulating food intake

Afferent signals regulating food intake

Analysis of the anorectic efficacy of HMR1426 in rodents and its effects on gastric emptying in rats

Antiobesity Therapy: Emerging Drugs and Targets

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