A concise synthesis of 1,4-dihydro-[1,4]diazepine-5,7-dione, a novel 7-TM receptor ligand core structure with melanocortin receptor agonist activity.

Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro-[1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-[1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119.

Discovery of small molecule agonists for the bombesin receptor subtype 3 (BRS-3) based on an omeprazole lead.

Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists.

Evidence in female rhesus monkeys (Macaca mulatta) that nighttime caloric intake is not associated with weight gain.

OBJECTIVE: To evaluate the hypothesis that nighttime consumption of calories leads to an increased propensity to gain weight. RESEARCH METHODS AND PROCEDURES: Sixteen female rhesus monkeys (Macaca mulatta) were ovariectomized and placed on a high-fat diet to promote weight gain, and we examined whether monkeys that ate a high percentage of calories at night were more likely to gain weight than monkeys that ate the majority of calories during the day. RESULTS: Within 6 weeks post-ovariectomy, calorie intake and body weight increased significantly (129 +/- 14%, p = 0.04; 103 +/- 0.91%, p = 0.02, respectively). Subsequent placement on high-fat diet led to further significant increases in calorie intake and body weight (368 +/- 56%, p = 0.001; 113 +/- 4.0%, p = 0.03, respectively). However, there was no correlation between the increase in calorie intake and weight gain (p = 0.34). Considerable individual variation existed in the percentage of calories consumed at night (6% to 64% total daily caloric intake). However, the percentage of calorie intake occurring at night was not correlated with body weight (r = 0.04; p = 0.87) or weight gain (r = 0.07; p = 0.79) over the course of the study. Additionally, monkeys that showed the greatest nighttime calorie intake did not gain more weight (p = 0.94) than monkeys that showed the least nighttime calorie intake. DISCUSSION: These results show that eating at night is not associated with an increased propensity to gain weight, suggesting that individuals trying to lose weight should not rely on decreasing evening calorie intake as a primary strategy for promoting weight loss.

Synthesis and structure activity relationship of guanidines as NPY Y5 antagonists.

A series of bis-aryl substituted guanidines have been discovered as potent NPY Y5 antagonists. The SAR and in vitro metabolic stability of these compounds are discussed.

The role of neuropeptide Y in the ovine fetal cardiovascular response to reduced oxygenation.

This study investigated the role of neuropeptide Y (NPY) in mediating cardiovascular responses to reduced oxygenation in the late gestation ovine fetus by: (1) comparing the effects on the cardiovascular system of an exogenous infusion of NPY with those elicited by moderate or severe reductions in fetal oxygenation; and (2) determining the effect of fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist on the fetal cardiovascular responses to acute moderate hypoxaemia. Under general anaesthesia, 14 sheep fetuses (0.8-0.9 of gestation) were surgically prepared with vascular and amniotic catheters. In 5 of these fetuses, a Transonic flow probe was also implanted around a femoral artery. Following at least 5 days of recovery, one group of fetuses (n = 9) was subjected to a 30 min treatment period with exogenous NPY (17 microg kg(-1) bolus plus 0.85 microg kg(-1) min(-1) infusion). In this group, fetal blood pressure and heart rate were monitored continuously and the distribution of the fetal combined ventricular output was assessed via injection of radiolabelled microspheres before and during treatment. The second group of fetuses instrumented with the femoral flow probe (n = 5) were subjected to a 3 h experiment consisting of 1 h of normoxia, 1 h of hypoxaemia, and 1 h of recovery during a slow I.V. infusion of vehicle. One or two days later, the acute hypoxaemia protocol was repeated during fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist (50 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion). In these fetuses, fetal arterial blood pressure, heart rate and femoral vascular resistance were recorded continuously. The results show that fetal treatment with exogenous NPY mimics the fetal cardiovascular responses to asphyxia, and that treatment of the sheep fetus with a selective NPY-Y(1) receptor antagonist does not affect the fetal cardiovascular response to acute moderate hypoxaemia. These results support a greater role for NPY in mediating the fetal cardiovascular responses to acute asphyxia than to acute moderate hypoxaemia.