Potential Therapeutic Applications

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Body Weight Regulation - NPY has potent effects on physiological and endocrine systems that modulate energy homeostasis (2,3,7). NPY has been identified as the most potent naturally occurring orexigenic peptide. Over the last few decades, it has been demonstrated in a number of species that administration of NPY to the brains of satiated animals induces a tremendous surge in food consumption (8,9). Although not entirely understood, this feeding response is thought to be mediated by the NPY Y1, NPY Y5 or both receptors, each of which is expressed in the hypothalamus. Central administration of NPY also lowers energy expenditure (10,11). Increased food consumption and decreased energy expenditure results in a state of positive energy balance that will promote adipose tissue accretion. Indeed, chronic central administration of NPY to normal rats results in a pathophysiological profile similar to that in human obesity, including hyperphagla, increased adiposity, hyperleptinemia, hyperinsulinemia and hypertriglyceridemia (12,13).

Several different lines of evidence indicate that endogenous NPY may play a key role in energy homeostasis. Fasting leads to a significant increase in NPY mRNA expression in the arcuate nucleus, and an increase in NPY itself in brain regions known to be involved in energy homeostasis, the arcuate nucleus and the paraventricular nucleus (14). This increased NPY synthesis and release may drive the hyperphagic response observed after fasting. The ob/ob mouse, the db/db mouse, and the Zucker rat, which are genetic models of early onset, spontaneous obesity, exhibit high levels of hypothalamic NPY mRNA and peptide (15,16). Thus, increased NPY transmission may be partially responsible for the extreme hyperphagia and morbid obesity in these rodents. Interestingly, the obese phenotype of the ob/ob mouse is attenuated when NPY is removed from the system, indicating that NPY is at least partially responsible for the massive obesity in the ob/ob mouse (17). However, results from other mutant mice in which either NPY or its receptors have been manipulated have been paradoxical. While mice overexpressing NPY

have an expected profile only when maintained on certain diets which promote obesity (18), NPY deficient mice have the same food intake, body weight, plasma corticosterone, insulin, and glucose levels as their wildtype counterparts (19). Mice lacking NPY Yi receptors have slightly diminished nocturnal and NPY-stimulated feeding, but refeeding after fasting was significantly decreased in the Yi -/- mice (20,21). However, Yi receptor deficient mice develop mild late onset obesity and moderate hyperinsulinemia, which could be due to the reduced locomotor activity observed in these mice. Thus far, data generated in mice lacking NPY Y5 receptors do not support a role for this receptor in mediating the effects of NPY on body weight regulation (22). Young NPY Y5 deficient mice have normal growth, feeding behavior, and body temperature. NPY Y5 deficient mice also unexpectedly develop mild late onset obesity, likely due to an increase in food intake. Ob/ob mice deficient for NPY Y5 were as obese as ob/ob mice, indicating that the attenuation of obesity in the ob/ob mouse lacking NPY is not mediated through the NPY Y5 receptor. Studies in the NPY Yi and Y5 knockout mice do indicate a role for these receptors in the increase in food intake following centrally administered NPY.

More recently, the NPY Y2 receptor has emerged as a potential player in energy homeostasis. Peripheral injection of PYY(3-36), an NPY Y2 agonist, reduced food intake and weight gain in rats and mice, but not in Y2 -/- mice. Ob/ob mice lacking the NPY Y2 receptor have reduced adiposity, hyperglycemia, hyperinsulinemia and have increased HPA axis activity (23). In addition, peripheral administration of PYY(3-36) to humans significantly reduced appetite and food intake (24).

Recent studies suggest that one mechanism by which NPY promotes a state of positive energy balance is through its inhibitory effects on the HPT axis (7,25). Centrally administered NPY to rats decreased circulating levels of the thyroid hormones T3 and T4, and suppressed proTRH mRNA synthesis, thus mimicking the effects of fasting. The actions of NPY on the HPT axis are mediated by hypothalamic Yi and Y5 receptors (26). Consistent with the inhibitory action of NPY on TRH release is the co-localization of GABA-ergic neurons expressing NPY immunoreactivity and TRH-producing neurons in the paraventricular nucleus (27).

Circadian Rhythm - The role of NPY in modulating circadian rhythm has recently been reviewed (28). NPY affects the mammalian circadian system in two ways: it can change the phase of the clock itself during the subjective day, and it can inhibit the phase shift normally caused by light during the subjective night. The change effected by NPY on circadian rhythm during the day is thought to be mediated by the NPY Y2 receptor, while the inhibition by light-induced phase shift at night appears to be mediated by the NPY Y5 receptor.

Anxiety and Depression - A large body of evidence has implicated a role for NPY and its receptors in psychiatric illnesses such as anxiety and depression, and this has been extensively reviewed (4,29). NPY is consistently reported to produce anxiolytic effects in a variety of anxiety/depression models, including punished responding tests, exploratory behavior models, social interaction and fear potentiated startle. The data support a strong role for the NPY Yi receptor in anxiety; however, involvement of other NPY receptors has not been ruled out.

Bone Formation - NPY is a down stream modulator of leptin action. Chronic central administration of NPY and leptin both have a similar inhibitory effect on bone mass. By comparing bone phenotypes of germline and selective hypothalamic Y2 receptor -deficient mice, it was reported that hypothalamic Y2 receptors are involved in a tonic inhibition of bone formation by alteration of autonomic activity in the bone (30). Y2 receptor deficient mice have an increased rate of bone mineralization, as well as stimulated osteoblast activity which leads to a two fold increase in bone volume. This rapid increase in bone volume after central deletion of Y2 receptors suggests that a Y2 receptor antagonist may be an effective treatment for the prevention of osteoporosis.

Congestive Heart Failure - Increased plasma levels of NPY are found in patients with cardiovascular disease, including hypertension and heart failure (31). Although a causal role for circulating NPY in these diseases has not been established, a correlation has been established between plasma NPY concentration and severity of left ventricular hypertrophy. NPY can contribute to cardiac hypertrophy via its hemodynamic effects on blood vessels through the NPY Y1 receptor (32). However, NPY can also produce cardiac hypertrophy by acting as a growth factor by directly activating p38, ERK and JNK in primary cardiomyocytes (33), or by potentiating the alpha-adrenergic agonist-induced activation of mitogen-activated protein kinase via the NPY Ys receptor (33). It has also been demonstrated that NPY can increase protein synthesis and/or inhibit protein degradation via NPY Y5 receptors in SHR cardiomyocytes (34). NPY Y5 receptors may therefore represent a novel therapeutic target for drugs designed to prevent or regress left ventricular hypertrophy.

Rhinitis and Nasal Congestion - Nasal obstruction and rhinorrhea present in allergic rhinitis are at least partly influenced by neuropeptides released from sensory, parasympathetic, and sympathetic nerves. NPY is co-localized with norepinephrine in sympathetic perivascular nerves. NPY is released with norepinephrine on sympathetic nerve stimulation and produces long lasting vasoconstriction of the nasal vascular bed through postsynaptic NPY Y1 receptors (35). In addition to direct vasoconstriction, there is evidence to suggest that NPY modulates the release of transmitters originating from parasympathetic and sensory nerves by acting on prejunctional NPY Y2 receptors. This would then attenuate the vasodilator response to the subsequent parasympathetic nerve stimulation in the nasal mucosa via non-adrenergic and non-cholinergic mechanisms (36). Putative therapeutic application of NPY in rhinitis has been recently suggested because intranasal administration of exogenous NPY in human beings reduces nasal airway resistance and vascular permeability without affecting submucosal gland secretion (37). Intranasal or intrabronchial pretreatment with a NPY Y2 receptor peptide agonist, (TASP-V), reduced nasal obstruction and bronchoconstriction evoked by histamine challenge in the pig; this agent also attenuated objective histamine-induced nasal obstruction in healthy volunteers (38). Therefore, NPY Y2 receptor agonists may have therapeutic applications in allergic rhinitis and asthma.

Pain - It has been reported that NPY modulates nociception at different levels in the central nervous system. At the spinal level, it was shown that intrathecal injection of NPY can be anti-nociceptive and pronociceptive in uninjured animals models depending on the dose due to biphasic dose-effect curves (39,40). Experiments with Y1 knockout mice suggest that Y1 receptors contribute to the antinociceptive effects of intrathecal NPY in rodent models of acute nociception (41). After experimentally-induced nerve injury, NPY gene expression is upregulated within the population of medium- and large-diameter DRG neurons of the A beta-fiber class and follows a time course which is consistent with the development of tactile hypersensitivity-induced allodynia (42). NPY microinjection into the n. gracilis of uninjured rats induced reversible tactile allodynia, but not thermal hypersensitivity, in the ipsilateral hindpaw. In addition, NPY anti-serum and the NPY Y1 receptor antagonist BIBO 3304 blocked nerve injury-induced tactile hypersensitivity, but not thermal hyperalgesia (43). These data suggest that NPY Y1 receptor antagonists may be useful for the treatment of nerve injury-induced tactile allodynia.

Alcohol Dependence - There is a growing body of evidence suggesting that NPY plays a major role in alcohol dependence. Alcohol consumption is elevated in NPY-

deficient mice, but decreased in transgenic mice that overexpress NPY (44). Alcohol consumption behavior was enhanced in mutant mice lacking the NPY Yi receptors, (45) but reduced in mutant mice deficient of NPY Y2 receptors (46). In addition, mutant mice without the NPY Y1 receptor were less sensitive to alcohol-induced sedation, whereas mutant mice lacking the NPY Y5 receptor had increased sleeping time without altering voluntary alcohol consumption behavior (45). Recently, it has been confirmed that icv administration of the selective NPY Y2 receptor antagonist, BIIE0246, can suppress alcohol self-administration in rodents, without affecting the consumption of a sweetened solution (47). These data suggest that a Y2 receptor antagonist might be a novel treatment for alcoholism.

This section will highlight structure-activity relationship (SAR) studies and pharmacological characterization of small molecule NPY receptor antagonists that have been reported recently. Most studies have focused on characterization of NPY Y1 and Y5 receptor antagonists as potential therapeutic agents for obesity management. There has been little recent activity with respect to selective NPY Y2 and Y4 receptor ligands.

NPY Y1 Receptor Lioands - Acute in vivo studies with the potent, orally active aminopyridine Y1 receptor antagonists J-104870 (1) and J-115814 (2} support a role for NPY Yi receptors in modulation of feeding behavior in rodents (48). Importantly, 2 suppressed feeding in wild-type mice, but not in NPY Yi receptor-deficient mice, supporting the Yi specificity of the compound (49). Recently 1 was evaluated chronically in obese Zucker rats (50). The compound is brain-penetrant, has high affinity for rat and human Yi receptors (K¡ of 0.51 nM and 0.26 nM, respectively), no significant affinity for human Y2, Y4 and Y5 receptors (K¡>6000 nM), and is a potent functional antagonist of Yi receptors (51). Administration of 1 to Zucker rats (100 mg/kg/day p.o.) for 2 weeks caused a reduction in food consumption which plateaued after 4 days, then gradually approached that of control animals. Body weight gain after 2 weeks was inhibited by 3% in treated animals relative to control animals. The inhibition in body weight gain was accompanied by a reduction in epididymal adipose cell size, normalization of plasma corticosterone levels, and reduced fat accumulation in the liver. Although these effects were observed at a relatively high dose, no overt adverse effects were discerned; however the difficulties in ruling out non-Yi receptor mediated mechanisms that might account for the anorectic effect were pointed out (50).

The structurally distinct pyrazolopyrimidine CP-671906 (3) displays high affinity for human and rat NPY Yi receptors (Ki of 1.5 nM and 3.5 nM, respectively) low affinity for NPY Y2 and Y5 receptors («¡>1,000 nM) and no significant binding against a panel of other receptors, enzymes and ion channels (52). The compound is a functional antagonist of NPY Yi receptors, and is orally bioavailable and brain penetrant in rats. Administration of a 40 mg/kg p.o. dose of 3 to rats inhibited feeding induced by NPY, but not spontaneous feeding or feeding induced by a Y5 receptor agonist (52). While the latter observations are consistent with a specific Yi receptor-

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