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NPY on the postsynaptic Y1 and Y5 receptors to produce the effects. In human trials, PYY3-36 infusion 2 h before an 'all you can eat' buffet reduced food consumption by approximately 30% compared to saline-infused control treatment.21 Intranasal administration of PYY3-36 is being pursued by several companies as a potential treatment for obesity.

6.18.8.5 Ghrelin Antagonists

Ghrelin is a stomach-derived 28-amino-acid peptide with an n-octanoyl modification of Ser3.21-23 It acts as the endogenous ligand for the GH secretagogue receptor (GHS-R). Ghrelin and GHS-R are also expressed in the hypothalamus and pituitary, where they modulate the secretion of GH from the pituitary as well as the secretion of CRF and vasopressin. Prominent among the biological effects of ghrelin is a pronounced orexigenic effect that, with repeated administration, can lead to obesity in preclinical models. In rodents, the feeding response to ghrelin appears to be dependent on NPY and AGRP, since immunoneutralization or administration of a receptor antagonist to these peptides abolished the acute orexigenic effects of ghrelin. Based on these experimental findings, an antagonist or inverse agonist to the GHS-R will be an interesting approach for the treatment of obesity. However, impairment of GH secretion and the consequent reduction in metabolism will warrant further study in the development of these agents.

6.18.8.6 Melanin-Concentrating Hormone Antagonists

The peptide MCH was originally identified in fish as a neurohypophyseal hormone that affects skin pigmentation in teleost fishes.21 In humans, MCH is a cyclic nonadecapeptide with high homology to the salmon MCH amino acid sequence. Subsequently, MCH was found to be an orexigenic peptide after central administration to rodents. Central administration of MCH into normal rats produces a marked increase in food intake, while fasting will increase the expression of mRNA encoding MCH in mice. In the hypothalamus of obese ob/ob mice, MCH mRNA is upregulated and fasting will further increase the expression. MCH produces its biological effects through two GPCRs called MCH1 and MCH2. Since MCH2 is not expressed by rodents, the MCH1 receptor has been studied more extensively. Peripheral administration of the small-molecule MCH1 receptor antagonist (SNAP 7941, Figure 13) has been reported to block food consumption induced by central MCH administration. Chronic administration to rats with dietary-induced obesity results in a significant and sustained decrease in body weight. In addition, this antagonist exhibited anxiolytic and antidepressant-like activity in preclinical models. Therefore MCH1 receptor antagonists may have broad therapeutic utility for the treatment of obesity, eating disorders, anxiety, and depression.

6.18.8.7 MC4 Receptor Agonists

The MC4 receptor is a GPCR for the endogenous hormone a-melanocyte stimulating hormone (a-MSH).18 The MC4 receptor is localized primarily in the brain and is highly concentrated in hypothalamic regions. Several lines of evidence implicate the system in the control of energy homeostasis. MC4 knockout mice demonstrate increased food consumption and increased adiposity, indicating that the tonic stimulation of the MC4 receptor is important in the regulation of food intake and body weight. Heterozygotes for the MC4 deletion also become obese but to a lesser degree compared to the homozygote. Subsequently, the gene for AGRP was identified based on homology to the Agouti protein, a protein that determines coat color in mice. This peptide was found to be an endogenous antagonist of MC3 and MC4 receptors. AGRP was subsequently localized to NPY-containing neurons within the arcuate nucleus of the hypothalamus and AGRP was found to be upregulated in this region by fasting and leptin deficiency. When centrally administered, AGRP increases appetite for up to a week. Finally, synthetic agonists of MC4 decreased food intake while synthetic antagonists of this receptor increase food intake. Therefore, it is likely that interplay between AGRP and a-MSH is important in the maintenance of body weight and composition. As such, the discovery and development of specific, centrally active MC4 agonists has become a high priority within the pharmaceutical industry.

6.18.8.8 Neuromedin U (NmU)

Neuromedin U (NmU) is a highly conserved neuropeptide and was originally isolated from porcine spinal cord.24 It is broadly distributed throughout the body, with particularly high levels found in the gastrointestinal tract and pituitary. Administration of NmU intracerebroventricularly or directly into the periventricular nucleus of the hypothalamus decreases feeding and increases gross locomotor activity, body temperature, heat production, and oxygen consumption in rats. NmU interacts with two receptor subtypes and it is not clear which receptor subtype mediates these effects, although expression of the NmU-R1 is found in the paraventricular nucleus. More recently, mice deficient in NmU were found to be obese. In addition peripheral administration of NmU has been shown to decrease food intake and body weight. Taken collectively, a NmU agonist may provide an innovative antiobesity agent that would decrease consumption and increase the metabolic rate.

6.18.8.9 Corticotropin-Releasing Factor, Urocortin I, II, and III

CRF was originally discovered as a hypothalamic factor involved in the regulation of the hypothalamic-pituitary-adrenal axis.25 This peptide is a 42mer and is highly concentrated in the hypothalamus and pituitary. Two GPCR subtypes (CRF1 and CRF2) were identified that mediated increases in intracellular cyclic adenosine monophosphate. The CRF1 receptor was found to mediate the stresslike endocrine and behavioral responses to centrally administered CRF. Subsequently, centrally administered CRF was found to decrease feeding and increase metabolism by interaction with the CRF2 receptor. However, deletion of neither the CRF1 nor CRF2 receptors in mice had any prominent effect on body weight. Homology screening using CRF and urotensin allowed the identification of three new related endogenous peptides, urocortin (Ucn) I, Ucn II, and Ucn III. Given the relatively low affinity of CRF for the CRF2 receptor, the high affinity that these three peptides display for the CRF2 receptor makes it likely that one or more of these peptides is the endogenous ligand for this receptor. Therefore, it will be interesting to evaluate these and more selective and stable CRF2 agonists in the regulation of feeding and metabolism.

6.18.8.10 Cocaine- and Amphetamine-Related Transcript

CARTwas originally discovered as an mRNA encoding an 89mer that was regulated by drugs of abuse in certain brain regions.26 Two C-terminal CART-derived peptides, CART 42-89 and CART 49-89, have been isolated from the rat hypothalamus and pituitary, although these fragments have not yet been observed in human samples. Central administration of CART and CART fragments decreases food intake, although the actual brain region responsible for this action is somewhat debated. CART also has effects on the control of normal movement which may complicate preclinical food intake studies. Following fasting, rats show a decrease in CART mRNA in the arcuate nucleus of the hypothalamus, while decreased CART expression was found in obese animals. However, the CART knockout mouse does not become obese on a normal diet and the receptor for this peptide is currently unknown. Further study will be required to appreciate fully the potential of this target for the treatment of obesity.

6.18.8.11 Bombesin and Related Peptides

Bombesin is a 14-amino-acid peptide originally isolated from the skin of an amphibian, Bombina bombina.18 In subsequent studies, large quantities of bombesin-like immunoreactivity were found in the CNS and gastrointestinal tract in various species. This immunoreactivity was not due to bombesin, since it is not expressed in mammals, but rather to the highly related mammalian peptides gastrin-releasing peptide (GRP) and neuromedins B and C. These peptides are collectively known as the bombesins and have a variety of actions on feeding, plasma levels of metabolic hormones, blood pressure, and hypothalamic-pituitary-adrenal function. Both central and peripheral administration of bombesin and GRP decrease food intake, suggesting these peptides may function as gut-brain-signaling molecules. The anorectic effects of bombesin and GRP have also been observed in humans, though the effect seems to be absent in obese individuals. At present, at least four different bombesin receptors (BB1-4) have been identified to date and these receptors can be subclassified into neuromedin B-preferring (BB1) or GRP-preferring (BB2). BB3 and BB4 exhibit low affinity for bombesin and the endogenous ligand for these receptors is currently unknown. Genetic deletion of the bombesin receptors in mice has led to some insight as to the potential molecular entities involved in feeding. Deletion of the BB1 and BB2 receptors does not result in any overt phenotype related to obesity. In the BB1 knockout mice, neither bombesin nor GRP suppresses glucose intake, suggesting this is the receptor involved in feeding. However, the lack of an overt phenotype suggests that GRP performs only a short-term role in satiety. Interestingly, the BB3 knockout exhibits an age-associated mild obesity with hypertension, glucose intolerance, and elevated insulin levels. The increased adiposity appears to be due to a reduction in energy expenditure without a change in food consumption or locomotor activity. These results suggest that the BB3 receptor may be a promising target for the discovery of novel antiobesity agents.

6.18.8.12 Enterostatin

Enterostatins are pentapeptides derived from N-terminal cleavage of pancreatic procolipase in the small intestine.18 Colipase serves as a protein cofactor for pancreatic lipase and is necessary for intestinal fat digestion. Enterostatin is absorbed from the gut and functions as a potent anorectic peptide to reduce fat consumption in rodents selectively. Three enterostatin amino acid sequences have been identified in rats and humans and are described by their single letter amino acid abbreviations: VPDPR (rat and human), APGPR (human), and VPGPR (rat). While all three of these peptides are capable of reducing food intake, little is known about the receptor(s) mediating these effects. The anorectic effect of enterostatin in preclinical models appears to require prior chronic ingestion of a high-fat diet. In addition, plasma concentrations of enterostatin have been correlated to fat preference in different strains of rats. The relevance of the preclinical findings to human obesity may be limited since intravenous enterostatin produced no effects on feelings of hunger, satiety, or food preference in a phase II, double-blind randomized crossover placebo-controlled study of 18 obese patients. Further advances in this area will be dependent on the identification of the receptor for enterostatins as well as a better understanding of the peptide's ability to penetrate the blood-brain barrier.

6.18.8.13 Orexins

Orexin-A and orexin-B are 33 and 28mers, respectively.18 These peptide sequences are the results of posttranslational processing of the same preproorexin peptide. These peptides were first identified in extracts of rat brain and bovine hypothalamus and were distinguished by their ability to evoke transient elevations of intracellular calcium concentrations in cells expressing an orphan GPCR now known as the orexin-1 or OX1 receptor. A second receptor (OX2) was identified based on sequence homology to the OX1 receptor. The OX1 receptor has higher affinity for orexin-A than orexin-B, while the OX2 receptor exhibits similar affinity for the two peptides. In general, orexin-A exhibits a greater orexigenic effect than orexin-B, though orexin-B appears to be more rapidly metabolized. While the absolute increase in food intake is not as great as observed with NPY or a GRP, increases in food intake are similar to those observed with galanin or MCH. Food deprivation has been demonstrated to increase orexin mRNA levels. Intracerebroventricular injection of an orexin-A antibody reduces food intake in fasted rats while a selective OX1 receptor antagonist (SB-334867, Figure 14) was reported to reduce food intake.

While the orexins were named for their effects on food intake, an important role for this peptide has been identified in the sleep-wake cycle. OX2 receptor knockout mice exhibit spontaneous sleep episodes similar to those observed in human narcolepsy. In addition, canine narcolepsy was associated with a mutation in the OX2 receptor gene. Based on these data, a compelling argument could be made for targeting the OX2 receptor for the development of therapeutics for sleep disorders and narcolepsy. While the OX1 receptor appears to be more involved in food intake, a role for the OX2 receptor cannot be excluded at this time. This is a very active area of research by a number of pharmaceutical companies and, hopefully, significant advances will be made in the discovery and development of selective antagonists in the coming years.

6.18.8.14 Cholecystokinin Agonists

Cholecystokinin (CCK) and CCK peptide fragments are synthesized and secreted from cells in the duodenum in response to nutrients in the lumen.22 The specific nutrients that are most effective in stimulating CCK secretion vary according to the species studied. CCK also functions to stimulate the exocrine pancreas and the gallbladder to facilitate ingestion. Administration of CCK before a meal will dose-dependently reduce meal size in a variety of species. Plasma CCK has a very short half-life and, therefore, is considered to be a short-term regulatory factor. In addition, the satiety-inducing effect of continuous intravenously administered CCK or CCK analogs rapidly desensitizes. CCK is believed to produce its biological effects through two GPCRs, CCK1 and CCK2. Rats with a spontaneous mutation of the CCK1 receptor (Otsuka Long-Evans Tokushima fatty rats) show increased meal size and increased body weight. In contrast, CCK1 receptor knockout mice have a normal body weight. Glaxo-Smith-Kline (GSK) has had an active program in developing nonpeptide CCK1 agonists for the treatment of obesity and for gallstone prophylaxis. However, the lead compound, GI181771, was recently discontinued following phase II trials that showed disappointing clinical efficacy for the treatment of obesity. Development of an earlier molecule discovered at Abbott laboratories, A-71623, has also been discontinued (Figure 15).

Figure 14 Orexin-1 receptor antagonist SB-334867.

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