Cannabinoid-1 receptor inhibition prevents the reduction of 24-hour energy expenditure with weight loss.

Pharmacologic inhibition of the cannabinoid-1 receptor (CB1R) in rodent models leads to weight loss and time-dependent changes in energy balance. This study evaluated the effects of CB1R inhibition on weight loss, energy expenditure (EE), and food intake (FI) in an obese canine model following 4 weeks of treatment. Eighteen maintenance-fed obese beagles were evenly and randomly allocated to a CB1R inverse agonist (AM251) (2 mg/kg), a 70% food-restricted (FR) diet, or a control group (C).

Biodegradation of the high explosive hexanitrohexaazaiso-wurtzitane (CL-20).

The aerobic biodegradability of the high explosive CL-20 by activated sludge and the white rot fungus Phanerochaete chrysosporium has been investigated. Although activated sludge is not effective in degrading CL-20 directly, it can mineralize the alkaline hydrolysis products. Phanerochaete chrysosporium degrades CL-20 in the presence of supplementary carbon and nitrogen sources.

1-Sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists for the treatment of obesity.

A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities.

Characterization of alpha(4)beta(1) (CD49d/CD29) on equine leukocytes: potential utility of a potent alpha(4)beta(1) (CD49d/CD29) receptor antagonist in the treatment of equine heaves (recurrent airway obstruction).

The purpose of this study was to characterize the alpha(4)beta(1) receptor (CD49d/CD29, very late antigen-4, VLA-4) on circulating equine leukocytes and to evaluate the intrinsic potency of an alpha(4)beta(1) receptor antagonist (Compound B) in the horse. Ultimately, these studies would allow us to determine the suitability of treating recurrent airway obstruction (RAO; heaves) affected horses by blocking the cellular recruitment of lymphocytes and neutrophils into the lung. The data demonstrates the alpha(4)beta(1) integrin is present on horse lymphocytes and neutrophils (fluorescence-assisted cell sorter, FACS) and can bind low molecular weight alpha(4)beta(1) antagonists (Compounds A and B) with high affinity.

Biodegradation kinetics of the nitramine explosive CL-20 in soil and microbial cultures.

The cyclic nitramine explosive CL-20 (C(6)H(6)N(12)O(12), 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12 -hexaazaisowurtzitane) is a relatively new energetic compound which could be a persistent organic pollutant. To follow its biodegradation dynamics, CL-20 was added to soil alone or together with organic co-substrates and N-source and incubated under oxic and anoxic conditions. Without co-substrates, the CL-20 degradation was detectable only under anoxic conditions.

The assessment of the energetic compound 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-Hexaazaisowurtzitane (CL-20) degradability in soil.

CL-20 is a relatively new energetic compound with applications in explosive and propellant formulations. Currently, information about the fate of CL-20 in ecological systems is scarce. The aim of this study is to evaluate the biodegradability of CL-20 in soil environments.

Aqueous solubility and alkaline hydrolysis of the novel high explosive hexanitrohexaazaisowurtzitane (CL-20).

The recently developed polycyclic nitramine CL-20 is considered as a possible replacement for the monocyclic nitramines RDX and HMX. The present study reports aqueous solubility data for CL-20, as well as the kinetic parameters for its alkaline hydrolysis with sodium hydroxide below and above its solubility limits. Aqueous solubility of CL-20 was measured in the temperature range of 4-69 degrees C and the data were fitted to a generalized solubility model.

Administration of a nonpeptidyl growth hormone secretagogue, L-163, 255, changes somatostatin pattern, but has no effect on patterns of growth hormone-releasing factor in the hypophyseal-portal circulation of the conscious pig.

The activity of the growth hormone secretagog, L-163,255, on growth hormone (GH), growth hormone-releasing factor (GRF), and somatostatin (SRIF) levels was evaluated in a porcine model of hypophyseal portal blood (HPB) collection. Young, castrated pigs had HPB and jugular blood collected for approximately 300 min. The blood collection was divided into discrete periods: baseline (BL) approximately 180 min; GH response period (RSP) approximately 90 min; and positive control period following a GRF bolus, 30 min.

Hypophyseal-portal concentrations of growth hormone-releasing factor and somatostatin in conscious pigs: relationship to production of spontaneous growth hormone pulses.

A method of collecting hypophyseal portal blood (HPB) in conscious pigs was used to show the relationship between GRF and somatostatin (SRIF) concentration and peripheral GH response. Six male castrate pigs (approximately 63 kg body weight) had HPB and jugular blood collected individually for an average of 175 min each. Twenty-seven spontaneous GH pulses were detected in the 1050 min of total HPB collection.

Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585.

To investigate the effect of hypophyseal transection (HST) on GH secretagogue activity of the non-peptidyl GH secretagogue L-692,585 in the conscious pig, male castrated swine were randomly assigned to either a hypophyseal stalk transection group (HST; n = 3) or to a sham-operated control group (SOC; n = 3). Treatments administered were L-692,585 (100 micrograms/kg), human GH-releasing factor(1-29)NH2 (GRF; 20 micrograms/kg) or L-692,585 (100 micrograms/kg) + GRF (20 micrograms/kg) on days -7 to -3 before surgery and days +3 to +8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-releasing hormone (CRH; 150 micrograms) or GnRH (150 ng/kg) both before and after surgery.