D Patel, N Patel
antagonist, metabolic disorders, neuropeptide y, npyy5 receptor, obesity
D Patel, N Patel. Contemporary Development In NPYY5 Receptor Antagonist. The Internet Journal of Pharmacology. 2008 Volume 7 Number 1.
The prevalence of obesity continues to increase throughout the world and the burden of obesity and related co morbidities is large. Contemporary consideration has focused on physiology of neuropeptide Y and its role in the regulation of energy homeostasis. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide YY5 receptor antagonist, have potentiality to bless the obesity patients worldwide. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. New leads are under research by major pharmaceutical companies to limit the side effects and explore the area to meet clinical requirement.
Obesity is defined as excess of adiposity for a given body size and results from a chronic imbalance between energy intake and energy expenditure, become the catastrophic illness to increase metabolic complication throughout the world. It increased the risk of diabetes, hypertension, dyslipidemias, cardiovascular disease, gallstone, osteoarthritis, certain forms of cancer and reduce the life expectancy  . Neuropeptide Y (NPY) is a neuropeptide made up of 36 amino acids with an amide in carboxy terminal position (pancreatic polypeptide family) originally discovered in extracts of porcine brain  . It is found in abundance in the central and peripheral nervous system, whose alterations provoke eating, emotional, cardiovascular, diabetes and other diseases  . NPY receptors are a family of seven transmembrane G protein coupled receptors (7t-GPCR), designated collectively as Y receptors that are expressed throughout the central and peripheral nervous systems  .
NPY can be found in most brain regions, particularly in the cortex, hippocampus, thalamus, hypothalamus and brainstem  . NPY, peptide YY and pancreatic polypeptide elicit their physiological effects by interacting with at least six distinct GPCR designated Y1, Y2, Y3, Y4, Y5 and Y6  . The structural differences among neuropeptide Y receptors is beneficial to drug discovery efforts since compounds with high affinity for a particular neuropeptide Y receptor are less likely to interact with other neuropeptide Y receptors. In addition to having distinct amino acid sequences, each of the neuropeptide Y receptors is characterized by a unique pharmacological profile and distinct tissue localization. The Y1 receptor was cloned and sequenced in 1992, the Y2 receptor and the Y4/PP1 receptor in 1995, and the Y5 receptor in 1996  . The term dNPY receptors have been retained even though NPY is not the preferred endogenous ligand for all Y receptors  . Y1, Y2 and Y5 bind preferentially NPY and PYY, whereas Y4 binds preferentially PP. Y1 and Y5 receptors exhibit similar high affinities for NPY, PYY and [Pro34]-substituted analogs of NPY or PYY (e.g., [Leu31, Pro34] NPY), but can be distinguished by the selective, nonpeptide Y1 antagonist, BIBP 3226  . Thus the efforts have been focused on Y1 or Y5 receptor selective antagonists. They are implicated in several biological roles including vasoconstriction, learning and memory and energy balance  . It is highly expressed in several regions of the brain and is released into the circulation from neuronal stores in times of stress. In the CNS, NPY has been implicated in feeding, anxiety and depression, endocrine function, and metabolism  . NPY is a powerful stimulant of food intake when administered directly into the hypothalamus.
Development Of Non-Peptide NYY5 Receptor Antagonists
The NPYY5 receptor was initially identified by molecular cloning. The NPYY5 receptor is pharmacologically distinguished by its high affinity for both N-terminally truncated analogues of NPY and [Pro34] peptide YY. Neuropeptide YY5 receptor mRNA is discretely localized in rat and human brain, primarily in piriform cortex, olfactory tubercle and hypothalamus  . NPYY5 receptor binding sites have also been detected in these regions, although some groups fail to detect neuropeptide YY5 receptor binding in hypothalamus  . The receptor most likely subtypes responsible for centrally mediated NPY induced feeding responses are NPY Y1 and NPY Y5  . There is now a significant body of primary and patent literature describing potent devoted to neuropeptide YY5 receptor antagonists reported. The following discussion focuses on the pharmacology of nonpeptidic NPYY5 receptor antagonists, with emphasis on reports from the primary literature that attempt to correlate neuropeptide YY5 receptor selective antagonism with effects on food intake and body weight.
The identification of the Y5 receptor as a potential feeding receptor subtype has stimulated a number of investigations in this area. In light of this conflicting evidence, the evaluation of structurally diverse compound classes remains important in order to better understand the role of the Y5 receptor in the control of appetite, and hence the potential utility of these compounds for the treatment of obesity. The initial evidence supporting the role of Y5 as an important regulator of feeding behavior include the positive correlation between the binding affinity of Y5 peptide agonists in vitro and there in vivo potency as orexigenic agents in animal feeding models  . For example, Novartis and Synaptic were the first to report a series of 2, 4-diaminoquinazolines and aryl sulfonamides as potent Y5 receptor antagonists  . Subsequently, a number of patents have also claimed a variety of compound classes that act at the Y5 receptor.
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Evidence from rodent studies suggests a potential therapeutic role for Y5 receptor antagonism in the treatment of human obesity and a number of good tool molecules with structurally diversity are available. However, the exact therapeutic potential associated to this biological target in obesity has still to be clarifies. The therapeutic potency of Y5 receptor antagonism in human might be smaller than other antiobesity drugs  .
Challenges In Development
Antagonism of NPY remains a tantalizing target, but it appears difficult to find a developable compound with a suitable pharmacology, and it has yet to be demonstrated that such a compound can reduce obesity in animals, let alone humans. A particular challenge will be to demonstrate anti-obesity activity in situations where leptin levels are high and NPY release is low  .
Most of the evidence in support of the Y5 hypothesis has been generated in rodents, but recently, there have been reports suggesting that Y5 antagonists have little or no effect in rodent feeding models  . NPY induced feeding was reduced in Y1 deficient mice while it was not significantly influenced in the Y5. The strongest support for the study in rhesus monkeys showing that icv, administration of Y5 antagonist attenuates NPY mediated feeding  .
Potential Side Effects Of Npy Receptor Antagonists
Because NPY is involved in a wide variety of physiological processes, many of which are mediated via NPY5 receptors, it is possible that NPYY5 receptor antagonists developed for the treatment of obesity will be associated with specific mechanism-based side effects. The latter effect presumably reflects effects of the neuropeptide YY1 receptor antagonist on pituitary gonadotropin secretion. All studies reported to date used i.c.v., administration of neuropeptide YY5 receptor antagonists and additional studies with newer, orally active, brain penetrant compounds would be more informative. Similarly, neuropeptide YY5 receptor activation has been associated with anti-epileptic effects, attenuation of opiate withdrawal, modulation of circadian rhythms, regulation of pituitary hormone secretion, natriuresis and decreases in plasma glucose  . Unfortunately, the effect of neuropeptide YY5 receptor antagonists on these processes has not been reported.
Summary And Perspective
Much of the data published on small non peptide molecule of various chemical classes, selective Y5 antagonists to date has been compiled using compounds that suffer from a variety of pharmacokinetic issues such as poor brain penetration, or short in vivo half-lives
The role of the NPYY5 receptor in energy homeostasis is less clear, however. Mice lacking the NPYY5 receptor do not differ from wild type mice in paradigms that assess food intake and body weight under a variety of conditions. Furthermore, the reported effects of NPYY5 receptor antagonists on food intake and body weight are conflicting. Although administration of some NPYY5receptor antagonists is associated with reduced food intake and body weight gain, evidence for the specificity of these effects is lacking. The lack of any consistent effect of NPYY5 receptor deficiency and NPYY5receptor antagonists on energy homeostasis suggest that the role of neuropeptide Y in the regulation of body weight is more complicated than previously envisioned. Overall, these results may indicate that the high level of redundancy in the regulation of body weight insures that mice can substantially compensate for the loss of a single neuropeptide or neuropeptide receptor under normal conditions. However, the data obtained to date suggests that NPYY plays a critical role in energy homeostasis under very specific physiological conditions, particularly conditions of real or apparent deprivation. These data indicate that NPYY receptor antagonists may be most useful in human conditions where appetite is increased and energy expenditure is decreased due to activation of the starvation response. Such conditions include obese patients who are dieting, formerly obese patients who have lost substantial weight, and patients with complete or partial leptin deficiency. Significant progress has been made in the identification of structurally diverse, orally bioavailable NPYY5 receptor antagonists that can cross the blood brain barrier. However, there is a clear need for further studies with both NPYY5 receptor antagonists in order to clarify their potential as anti-obesity agents. Most studies have been performed in lean rodents or in genetically obese rodents that do not mimic common obesity in the human population. It would be desirable to evaluate the effects of compounds in diet-induced obese rodents and non-rodents as disease models that more closely mimic human obesity. Other critical issues in the development of NPYY receptor antagonists as effective agents for obesity management are the need to overcome counter balancing effects of the multiple complementary mechanisms involved in energy homeostasis that tend to oppose any changes in body weight and the identification of patient subclasses most likely to benefit from treatment. In summary, numerous investigations to date suggest that NPY is implicated in the pathophysiology of a number of diseases including feeding and metabolic disorders, anxiety, seizures, memory, circadian rhythm, drug addiction, pain, cardiovascular diseases, rhinitis, and endothelial cell dysfunctions. Thus, the design of selective antagonists of NPYY5 receptors could be useful compounds for the treatment of metabolic diseases like obesity. But large tissue distribution of NPY receptors and their stimulation or blockade could produce untoward effects which must be overcome to produce effective and safe drug.
Authors are highly grateful to Dr. R. K. Goyal for suggestion in preparation of review and Dr. K. P. Modi for discussion for presentation of matter.