Current Topics in Medicinal Chemistry - Volume 7, Issue 17, 2007

My daughter was borne in 1980, surely a good omen! At about the same time, I joined the University of Cincinnati as a fellow, and was looking for a new project in the GI hormone field and, coincidentally Tatemoto, the Man with Gold Fingers, added neuropeptide Y (NPY) and peptide YY (PYY) to his long list of polypeptide hormone discoveries. Since then, I have been working on NPY family of hormones and NPY peptides which, in turn, have served me well to date. The latter may also be true for most of my colleagues all over the world, who are privileged to meet every couple of years at the International Meetings on NPY. To be honest, I do not know much of anything else beyond NPY, Cincinnati, and my family! NPY (isolated from brain), PYY (isolated from intestine) and pancreatic polypeptide (PP) (isolated from pancreas) constitute the NPY/PP family of homologous hormones. Since its isolation, NPY has been described in various ways, depending on the site and function investigated. Some of these characterizations reveal normally reserved scientists reaching for superlatives: “NPY is the most abundant peptide in the brain;” “NPY is the most potent vasoconstrictor peptide isolated to date,” “NPY is the most powerful orexigenic peptide isolated to date.” These remarkable properties of NPY, especially the latter, spurred vigorous investigation of the properties of the NPY family of hormones. The last two and a half decades have seen the cloning of four functional receptors, denoted Y1, Y2, Y4 and Y5, the development of several useful receptor-specific ligands and the establishment of knock-out models for NPY and its various receptors. These tools have played key roles in delineating the receptor subtypes mediating various actions of NPY and also have provided strong evidence for the involvement of the NPY family of hormones in the pathophysiology of various conditions including obesity, cardiovascular and cardiac diseases, intestinal dysfunction, epilepsy and mental disorders. Thus, NPY receptors became obvious targets for drug development in the treatment of a variety of diseases. Moreover, a few pharmaceutical companies have recently initiated preliminary clinical or Phase I trials to determine whether NPY peptides have potential as anti-obesity drugs. For these reasons, the time is now appropriate for a special volume of Current Topics in Medicinal Chemistry dedicated to the “Potential of NPY Receptors as Targets in Drug Discovery.” In compiling this Special Volume on NPY, I have gathered contributions from experts on receptor targets that have been implicated unequivocally in diseases. In addition, I have also included chapters on emerging drug targets. A total of ten articles, including chapters on the clinical potential of NPY and its receptors in mental disorders, obesity, epilepsy, GI disorders, cancer, cardiac and cardiovascular diseases, and inflammatory and immune diseases are included in this volume. One of these chapters also describes how central leptin gene therapy could be exploited to beneficially alter hypothalamic NPY function. After a brief introduction, each chapter, based on the existing evidence, discusses the rationale(s) for developing NPY-based drugs, the receptor subtypes involved and the type of ligands (agonist/antagonist) that need to be developed. Most chapters conclude with a prospective of using NPY-based drugs to treat the concerned disease. In summary, this state-of-the-art volume on NPY Receptors as Targets for Drug Discovery will not only stimulate further research on the Clinical Potential of NPY, but will also serve as a “One-Stop Guide” on NPY-based drugs for those entering this field. I am certain that, with the advancement in peptidic- and non-peptidic drug delivery techniques, NPY based drugs will eventually be developed to treat a variety of diseases. I wish to express my sincere appreciation to all the authors for their outstanding contributions, and particularly for meeting their deadlines. I also thank Allen Reitz, Editor-in Chief, for asking me to edit this Special Volume on NPY.

Extensive preclinical studies suggest neuropeptide Y (NPY) to be involved in stress regulation and coping. NPY counteracts the behavioral consequences of stress and anxiety to maintain emotional homeostasis. NPY is also involved in learning, memory, and cognition, all of which are dysregulated in many psychiatric states. Dense localization of NPY and NPY receptors is found in brain areas implicated in psychopathology such as the amygdala, hippocampus, neocortex, septum, caudate-putamen, hypothalamus and locus coeruleus. Impaired central NPY signaling may therefore be involved in the pathophysiology of depression, anxiety, schizophrenia, alcoholism, and trauma-induced disorders like PTSD. Studies on the readily accessible plasma from psychiatric patients have provided some information on the relevance of NPY as a marker for sympathetic tone in certain conditions. Reports on cerebrospinal fluid (CSF) NPY in subjects with depression indicate a dysregulation of central NPY in this disorder, however, other conditions still need to be investigated.

A substantial amount of experimental evidence implicates neuropeptide Y (NPY) in the pathophysiology of epilepsy. Over the past 20 years, remarkable progress has been made in unraveling the mechanisms and receptors involved in the anticonvulsant effect of this abundantly expressed neuropeptide. Activation of Y2 and/or Y5 receptors and blockade of Y1 receptors in the central nervous system suppresses seizures in a variety of animal seizure models. Orally available, brain penetrating Y2 and/or Y5 agonists, and possibly Y1 antagonists, may therefore constitute a novel class of antiepileptic drugs, which could greatly benefit patients with medically refractory epilepsy. Significant progress has been made in identifying non-peptidergic Y1 antagonists that fulfill these criteria, but suitable Y2 and/or Y5 agonists have proven to be more elusive. Innovative oral and parental drug delivery strategies which are currently under development may offer a means of using the more readily available peptidergic NPY receptor ligands in a clinical setting. Finally, gene therapy, antisense probes or RNA interference strategies which alter the expression of NPY or its receptors in specific brain regions may also be of use in the treatment of epilepsy, but will probably benefit a smaller subgroup of epilepsy patients, since they typically require an invasive procedure.

A minute-to-minute crosstalk between the hypothalamic neuropeptide Y (NPY) network and the hormone leptin is essential for energy homeostasis. Leptin insufficiency i.e. lack of leptin restraint due to genetic and environmental factors on the hypothalamic NPY system confers obesity, a cluster of metabolic afflictions and shorter lifespan. A state-of-the-art gene transfer technology using recombinant adeno-associated viral vector to overcome hypothalamic leptin insufficiency was employed in rodent models of obesity, metabolic syndrome and shorter lifespan. Our findings show that life-long tonic repression of NPY system with a stable increase in leptin availability in the hypothalamus prevented the age-related and high fat-diet-induced obesity, hyperinsulinemia and diabetes and extended lifespan. Additional health benefits include increased energy expenditure and normalization of neuroendocrine control on reproduction, and promotion of brain and bone growth. We propose that central leptin gene therapy or novel long-acting leptin mimetics should be tested clinically to decelerate the worldwide epidemic of obesity, diabetes and shortened lifespan.

The peptides pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY) share a similar structure, known as PP-fold. Within this family of peptides, NPY, a highly conserved 36-aminoacid residue peptide, is involved in the regulation of a wide range of physiological functions, such as food intake and energy metabolism, as well as in the promotion of some remarkable aspects of tumor progression, including cell proliferation, matrix invasion, metastatization, and angiogenesis. NPY exerts its biological effects through five G-protein coupled receptors, named Y1-, Y2-, Y4-, Y5-, and y6-R, which appear associated with different aspects of oncogenesis. Y1-R seems involved in the modulation of cancer cell proliferation, whereas Y2-R activation appears to promote angiogenesis. The development of NPY receptor subtype selective analogs has helped to elucidate the physiological and pathophysiological role and localization of each receptor and may contribute to a better understanding of the receptor-ligand interaction. The NPY system appears to be variously associated with specific tumors, including neural crest-derived tumors, breast and prostate cancers. In addition to NPY, PYY is also able to affect cancer cell growth in a dose-dependent manner and through Y-Rs. In conclusion, peptides of the NPY family and the related receptors play an important role in the progression of different cancer types, with some molecular specificity according to each step of this process. On this basis, future studies may be directed to the implementation of novel diagnostic and therapeutic approaches targeting this system.

Hypertension-induced left ventricular hypertrophy (LVH), along with ischemic heart disease, result in LV remodeling as part of a continuum that often leads to congestive heart failure. The neurohormonal model has been used to underpin many treatment strategies, but optimal outcomes have not been achieved. Neuropeptide Y (NPY) has emerged as an additional therapeutic target, ever since it was recognised as an important mediator released from sympathetic nerves in the heart, affecting coronary artery constriction and myocardial contraction. More recent interest has focused on the mitogenic and hypertrophic effects that are observed in endothelial and vascular smooth muscle cells, and cardiac myocytes. Of the six identified NPY receptor subtypes, Y1, Y2 and Y5 appear to mediate the main functional responses in the heart. Plasma levels of NPY become elevated due to the increased sympathetic activation present in stress-related cardiac conditions. Also, NPY and Y receptor polymorphisms have been identified that may predispose individuals to increased risk of hypertension and cardiac complications. This review examines what understanding exists regarding the likely contribution of NPY to cardiac pathology. It appears that NPY may play a part in compensatory or detrimental remodeling of myocardial tissue subsequent to hemodynamic overload or myocardial infarction, and in angiogenic processes to regenerate myocardium after ischemic injury. However, greater mechanistic information is required in order to truly assess the potential for treatment of cardiac diseases using NPY-based drugs.

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that acts on multiple receptors (Y1-Y6) and exerts a variety of cardiovascular effects. Originally known as a vasoconstrictor acting on Y1 receptors, NPY is also a potent angiogenic factor as well as a powerful stimulator of vascular smooth muscle proliferation and atherogenesis in vitro and in vivo. These two types of vascular remodeling are predominantly mediated by Y2/Y5 and Y1 receptors respectively, but evidence suggests that all receptors are activated in both conditions. A strategy to inhibit neointima formation and atherosclerotic lesions without impairing ischemic angiogenesis and collateral vessel formation has been a major challenge to overcome. Studies in rodents show that Y1 receptor antagonist inhibits angioplasty-induced atheroscleroticlike vascular remodeling, without affecting ischemic revascularization. Conversely, Y2 receptor activation appears to be sufficient to stimulate angiogenesis in various animal models. Thus, the use of selective receptor agonists to promote angiogenesis through the Y2 receptor while antagonizing the pro-atherosclerotic and pro-stenotic effects with Y1 receptor-selective antagonists may help to successfully treat vascular remodeling in cardiovascular diseases.

The neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) family of hormones exhibit a wide variety of biological actions on the mammalian gastrointestinal tract through known G-protein coupled receptor pathways. At least four receptor subtypes, denoted as Y1, Y2, Y4 an Y5, each with specific affinities to NPY ligands, serve as regulators of mucosal function, gastrointestinal motility and secretion. Investigations to date, however, have implicated the NPY peptides as mediators in the pathogenesis of numerous gastrointestinal disorders, including malabsorption, short gut, inflammatory bowel diseases, and forms of pancreatitis. Our understanding of these diseases and the interactions of NPY peptides have been advanced by the development of receptor agonists and antagonists that can be used experimentally in animal models. Potent selective PYY agonists have been developed that exhibit clinical potential as proabsorptive agents. NPY receptor agonists and antagonists as well as mice harboring null mutations in the Y1 and Y4 receptors have provided novel approaches in preventing intestinal inflammation and diarrhea. The use of competitive antagonists and Y2 receptor knockouts have also aided in understanding secretory tone and electrogenic ion transport in the colon. In the pancreas, PYY suppresses amylase and cytokine release, which would be desirable in the clinical therapy of pancreatitis. Protein/DNA array analysis has revealed that PYY reduces transcription factor binding activity and disrupts signal transduction pathways activated by TNF-α in acinar cells. The present review gives an overview of NPY research in gastrointestinal disease and discusses its clinical relevance and potential use as therapy.

A combination of pharmacological and genetic studies in mice confirmed that the Y1 and Y5 receptors mediate the potent orexigenic actions of exogenous NPY. Although the physiological role of NPY in causing obesity is less clear, potent and selective antagonists of both Y1 and Y5 have been developed. Some of the NPY antagonists have suitable pharmokinetic (PK) properties that allowed them to be evaluated in various rodent models of obesity. Several different Y1 and Y5 antagonists cause weight loss in rodent models, though confirmation that these effects are mechanism based has been limited. One Y5 antagonist, MK-0557 was evaluated in a 1-yr clinical trial and found to cause modest weight loss. Optimal NPY antagonist therapeutics for obesity may require blockade of both the Y1 and Y5 receptors.

Neuropeptide Y (NPY), a potent orexigen peptide widely produced and distributed in arcuate neurons in the hypothalamus, is a promising candidate for the control of appetitive ingestive behavior. In mammals, the signaling is mediated via at least five different cell surface receptors, denoted as Y1, Y2, Y4, Y5 and Y6. Obesity is an important public health problem in the world, particularly in developed societies, and has taken on pandemic proportions. The therapeutics of obesity, including appetite suppressants, has increased 453% over the past decade, although issues concerning safety, efficacy, and little knowledge of the pharmacological activity result in the still modest effects of the anti-obesity drugs presently used. Ligands for Y receptors may be of benefit for the treatment of obesity, and recent findings have indicated a promising role of Y2 and Y4 in protecting against diet-induced obesity. This review highlights the supporting evidence therapeutic potential of Y2 and Y4 receptors antagonists as additional intervention to treat human obesity.

Growing evidence suggests that neuropeptide Y (NPY) plays an important role in the immune system. NPY is produced by the central and peripheral nervous system but also by immune cells in response to activation. NPY has pleiotropic effects on both the innate and adaptive arms of the immune system, with effects ranging from the modulation of cell migration to macrophage, T helper (Th) cell cytokine release, and antibody production. Subsequent studies have confirmed the importance of this system in immunity in particular via the demonstration that Y1, a receptor for NPY, plays a fundamental role in autoimmunity and inflammation using Y1-deficient animals. Furthermore, clinical studies have suggested a role for NPY in other immune disorders such as asthma and arthritis. This review provides the latest information on the role of NPY and Y1 in the immune system, and discusses the potential new opportunities of this work for the development of a new generation of immuno-modulatory treatments of autoimmune and inflammatory diseases.

Approaching a magic bullet? Less than a decade ago, the Food and Drug Administration (FDA) approved the first kinase inhibitor, Gleevec™, for chronic myelogenous leukemia (CML) and later for gastrointestinal stromal tumors (GIST). Gleevec, acting on the bcrabl oncogene, was hailed as a magic bullet due to its perceived selectivity profile as a targeted therapy agent versus traditional chemotherapy [1]. Since the landmark 2001 approval of Gleevec™ [2], seven more kinase inhibitors have been added to the anti-cancer arsenal. These include Sutent™ for renal cell carcinoma (RCC) and GIST [3], Nexavar™ also for RCC [4], Iressa™ for non-smallcell lung cancer (NSCLC) [5], Tarceva™ for NSCLC and pancreatic cancer [6], Torisel™ for RCC [7], and Sprycel™ for CML [8]. In March, the FDA approved Tykerb™, the first small molecule kinase inhibitor indicated for the treatment of breast cancer [9]. Tykerb™ treatment is indicated in combination with Xeloda™, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress Her-2 (also called ErbB2) and who have received prior therapy with taxanes, anthracycline, and Herceptin ™. Her-2 is responsible for stimulating tumor cell growth, found in excessive amounts in about 30% of primary breast cancers, and generally indicates poor prognosis. The Erb family proteins are well-precedented targets in oncology therapy with two commercial monoclonal antibodies (Herceptin™ and Erbitux™) on the market. Herceptin™, is the front-line therapy for breast cancer in women whose tumors overexpress the Her-2 gene [10]. Erbitux™ targets inhibition of EGFR (also called ErbB1) and is indicated for the treatment of colorectal and head and neck cancers [11]. Tykerb™ targets both of these key proteins involved in cancer. Whereas Herceptin™ targets Her-2 through a cell surface receptor, the small molecule Tykerb™ can enter the cell to inhibit the intracellular kinase domain. This difference in mechanism of inhibition may explain why Tykerb™ works in some Her-2 positive breast cancer patients that are no longer benefiting from Herceptin™ treatment [12]. Unlike other approved kinase inhibitors, Tykerb™ and Gleevec™ bind to an “inactive-like” kinase conformation [13]. Binding to “inactive-like” kinase conformations may provide some advantages for blocking biological activity through mechanisms related to the overall signal transduction process. In addition, Tykerb™ has a very slow off-rate from the purified intracellular domains of EGFR and ErbB2 compared with other Erb family kinase inhibitors [14]. The slow off-rate, inactive-like binding, and dual ErbB1/ErbB2 inhibition may provide Tykerb™ an attractive efficacy profile. Despite the abundance of recent approvals, the 600 registered clinical trials of kinase inhibitors for use in cancer (www.clinical trials.gov), and the many success stories, further research is needed to maximize the value of these therapies since no magic bullet has been uncovered for this complex area [15]. REFERENCES [1] Verweij, J.; Judson, I.; van Oosterom, A. STI571: a magic bullet? Eur. J. Cancer 2001, 37, 1816-1819. [2] a) FDA approves Gleevec for leukemia treatment FDA consumer 2001, 35(4), 6. b) Dagher, R.; Cohen, M.; Williams, G.; Rothmann, M.; Gobburu, J.; Robbie, G.; Rahman, A.; Chen, G.; Staten, A.; Griebel, D.; Pazdur, R. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin. Cancer Res. 2002, 8(10), 3034-3038. [3] Rock, E.; Goodman, V.; Jiang, J.; Mahjoob, K.; Verbois, S.; Morse, D.; Dagher, R.; Justice, R.; Pazdur, R. 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