5-Hydroxytryptamine (5-HT) 2C receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT 2C full agonist. Lorcaserin bound to human and rat 5-HT 2C receptors with high affinity (K i ϭ 15 Ϯ 1 nM, 29 Ϯ 7 nM, respectively), and it was a full agonist for the human 5-HT 2C receptor in a functional inositol phosphate accumulation assay, with 18-and 104-fold selectivity over 5-HT 2A and 5-HT 2B receptors, respectively. Lorcaserin was also highly selective for human 5-HT 2C over other human 5-HT receptors (5-HT 1A , 5-HT 3 , 5-HT 4C , 5-HT5 5A , 5-HT 6 , and 5-HT 7 ), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT 2A agonist (Ϯ)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT 2A agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT 2C -selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT 2A antagonist (R)-(ϩ)-␣-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL 100,907), demonstrating mediation by the 5-HT 2C receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT 2C receptor, with potential for the treatment of obesity.Serotonin mediates its physiological effects through at least 14 different receptors. The serotonin 5-HT 2 receptor subfamily contains three distinct receptor subtypes, 5-HT 2A , 5-HT 2B , and 5-HT 2C , all of which share considerable sequence homology (Ͼ80% in transmembrane spanning regions) and activate common signaling pathways, including G q ␣-mediated stimulation of phospholipase-C␤, elevation of intracellular inositol phosphates, and elevation of intracellular calcium (Roth et al., 1998). Human 5-HT 2C receptors are predominately expressed in the CNS, and they are highly enriched in choroid plexus, prefrontal cortex, hippocampus, basal ganglia, and other brain regions associated with the control of mood, cognition, and appetite (Roth et al., 1998). Thus, 5-HT 2C receptors have been proposed as a therapeutic target for the treatment of CNS disorders, including epilepsy, obsessive compulsive disorder, Parkinson's disease, schizophrenia, depression and anxiety, sleep disorders, and drug abuse (Tecott et al

There is no correlation between protein-precipitating capacity and either total phenolic or proanthocyanidin content of extracts of mature foliage from six species of oaks: Quercus alba (white oak), Q. bicolor (swamp white oak), Q. macrocarpa (bur oak), Q. palustris (pin oak), Q. rubra (red oak), and Q. velutina (black oak). It is argued that studies which probe the role of tannins in the selection and utilization of food by herbivores should include a protein-precipitation assay, since such an assay provides a measure of the property of tannins which is presumed to contribute to their utility as defensive compounds. A convenient modification of the bovine serum albumin (BSA) precipitation assay, which measures the amount of protein precipitated when a plant extract is added to a BSA solution, is described. Advantages of this procedure recommend its routine adoption in studies of the role of tannins in plant-herbivore interactions.

The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.

Abstract-Relative growth rate and relative nitrogen accumulation rate for fifth-instar Spodoptera eridania larvae vary less than 20% on artificial diets in which protein content varies more than 250%, due to compensatory adjustments in consumption rate and changes in efficiencies of food and nitrogen utilization. The substitution of zein for two-thirds of the casein in a diet containing 26.0% protein results in a 25% decrease in both relative growth and nitrogen accumulation rates, due to reduced values of relative consumption rate, relative nitrogen consumption rate, approximate digestibility, approximate digestibility of nitrogen and efficiency of conversion of digested nitrogen. Although larval growth rate is relatively independent of diet nitrogen, larval composition is highly dependent upon both nitrogen quantity and quality. As diet nitrogen increases, larval nitrogen content increases and fat content decreases. Larvae on diets containing a mixture of casein and zein produce 3.53.9 times as much uric acid and respire at rates significantly higher than larvae on diets containing the same total amount of protein but lacking zein. Thus, there is a measurable metabolic cost associated with processing low quality protein. We conclude, however, that elevated metabolic rates of larvae on diets containing nutritionally unbalanced protein are not the cause of reduced growth rates. On these diets, growth is limited by an amino acid present in limiting quantities, and the elevated metabolic rate is due, at least in part, to increased synthesis of uric acid.Finally, we discuss the possibility that variation in amino acid profiles across host plant species might be a factor favouring specialization in insect herbivores.Key Word Index: Southern armyworm, Spodoptera eriaimia, growth, nutritional indices, food utilization, nitrogen budget, uric acid production, respiration rate, metabolic cost INTRODUCHONThe nutritional quality of a protein is a function ofThe importance of dietary nitrogen as a factor influits amino acid composition.The critical importance encing both the fitness of individual herbivorous of the amino acid composition of the diet to growth insects and the dynamics of insect populations has and reproduction in insects has been elegantly docubeen extensively documented (Slansky and Feeny, mented in studies of several species of aphids (Dadd and Krieger, 1968;Retnakaran and Beck, 1968; van 1977;McNeil1 and Southwood, 1978;Mattson, 1980;Emden, 1972; Carter and cole, lg77), adult Lee er al., 1983;Scriber, 1984). According to Scriber (1984), the literature contains "at least 115 different mosquitoes (Briegel, 1985), and larvae of the comstudies in which insect damage, growth, fecundity, or mercial silkworm moth Bombyx mori (Horie and numbers increased with increased plant nitrogen". In Inokuchi, 1978;Horie and Watanabe, 1983).the same review, however, Scriber notes that "at least Schroeder and Malmer (1980) (Rodriguez et 1970;Watson and Creaser, 1975; Yeoh and Watson, al., 1970;Hare, 1983;Horie and Watanab...

I. Cellulose digestion hns been demonstrated in the Thysanura (Lepismatidae), Orthoptera (Cryptocercidae, Blattidae). Isoptera (Mastotermitidae. Kalotermitidae. Hodotermitidae, Rhinotermitdae. Termitidae). Coleoptera (Buprestidae. Anobiidae. Scarabaeidae, Cerambycidae), and Hymenoptera (Siricidne). 2. In all but the scarab beetles. cellulose digestion is brought about by a complex of three types of