Neuropeptide Y

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Identifiers
Aliases|
External IDs| GeneCards: [1]
Orthologs
Species| Human| Mouse
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Neuropeptide YIdentifiers

CAS Number|

* 82785-45-3 N

ChemSpider|

* none

ChEMBL|

* ChEMBL267633 N

E number| {{#property:P628}}
ECHA InfoCard| {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula| C190H287N55O57
Molar mass| 4253.7 g/mol
NY (what is this?) (verify)

Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the mammalian central nervous system, which consists of the brain and spinal cord. It is secreted alongside other neurotransmitters such as GABA and glutamate.[1][2][3][4]

In the autonomic system it is produced mainly by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue.[5] In the brain, it is produced in various locations including the hypothalamus, and is thought to have several functions, including: increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures.[4][6]

## Contents

* 1 Function
* 1.1 Cell growth
* 1.1.1 Dentate gyrus
* 1.1.2 Sub-ventricular zone
* 1.1.3 Olfactory bulb
* 2 Discovery
* 3 Connection to food intake
* 4 Connection to obesity
* 5 Clinical significance
* 5.1 Alcoholism
* 5.2 Stress and anxiety
* 6 See also
* 7 References
* 8 External links

## Function

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Neuropeptide Y has been identified as being synthesized in GABAnergic inhibitory neurons and acts as a neurotransmitter during cellular communication. Neuropeptide Y is majorly expressed in interneurons.[7] NPY exerts most of its effects through G-protein coupled receptor proteins, mainly Y1, Y2, Y4, and Y6.[3][4] All receptors have been indicated as participants in post-synaptic transmission activity, but the Y2 receptor has also been found to be involved in pre-synaptic processing.[2]

The receptor protein that NPY operates on is a G protein-coupled receptor in the rhodopsin like 7-transmembrane GPCR family. Five subtypes of the NPY receptor have been identified in mammals, four of which are functional in humans.[8] Subtypes Y1 and Y5 have known roles in the stimulation of feeding while Y2 and Y4 seem to have roles in appetite inhibition (satiety). Some of these receptors are among the most highly conserved neuropeptide receptors.

High concentrations of Neuropeptide Y synthesis and action have been found in the hypothalamus and hippocampus, specifically in the arcuate nucleus (ARC) and dentate gyrus. The arcuate nucleus has been found to have one of the highest concentrations of NPY. This allows NPY to regulate neuroendocrine release of various hypothalamic hormones such as luteinizing hormone.[9] Neuropeptide Y1 receptors have been found in highest density in the dentate gyrus along with a variety of other brain areas.[10]

### Cell growth

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Neuropeptide Y has been indicated as playing an important role in cell neurogenesis in various parts of the brain. Two particular brains areas of where NPY effects neurogenesis are the sub-ventricular zone and the dentate gyrus of the hippocampus. These areas are where cell growth and proliferation occur into adulthood.[11]

#### Dentate gyrus

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The dentate gyrus is significantly involved in cell proliferation, a process modulated by various internal factors including Neuropeptide Y. Reduction or elimination of NPY released by interneurons decreased cell growth in this brain area. NPY affects neurogenesis by interacting with ERK kinase signaling pathways.[12] Additionally, NPY acting on and stimulating Y1 receptors present on progenitor cell membranes in order to increase cell proliferation.[11]

#### Sub-ventricular zone

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Similar to the dentate gyrus, NPY has been found to increase cellular proliferation and differentiation in the sub-ventricular zone by specifically activating Y1 receptors in the ERK1/2 pathway. Additionally, NPY was found in neuronal fibers that pass through the sub-ventricular zone and extend to other brain areas. A variety of other effects and physiological processes involving NPY in the sub-ventricular zone have been discovered, many of which involve neuron migration patterns.[13]

#### Olfactory bulb

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It was found that after blocking NPY expression in mouse olfactory epithelium, the amount of olfactory precursor cells decreased by half. This in turn caused the mice to develop a lower amount of olfactory cells overall. This study exemplified NPY's influence on precursor cells.[14]

## Discovery

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Following the isolation of neuropeptide-y (NPY) from the porcine hypothalamus in 1982, researchers began to speculate about the involvement of NPY in hypothalamic-mediated functions. In a 1983 study, NPY-ergic axon terminals were located in the paraventricular nucleus (PVN) of the hypothalamus, and the highest levels of NPY immunoreactivity was found within the PVN of the hypothalamus.[15]

Six years later, in 1989, Morris et al. homed in on the location of NPYergic nuclei in the brain. Furthermore, in situ hybridization results from the study showed the highest cellular levels of NPY mRNA in the arcuate nucleus (ARC) of the hypothalamus.[16]

In 1989, Haas & George reported that local injection of NPY into the PVN resulted in an acute release of corticotropin-releasing hormone (CRH) in the rat brain, proving that NPYergic activity directly stimulates the release and synthesis of CRH.[17]

The latter became a hallmark paper in NPY studies. A significant amount of work had already been done in the 1970s on CRH and its involvement in stress and eating disorders such as obesity.[18] These studies, collectively, marked the beginning for understanding the role of NPY in orexigenesis or food intake.

## Connection to food intake

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Behavioral assays in orexigenic studies, in which rats are the model organism, have been done collectively with immunoassays and in situ hybridization studies to confirm that elevating NPY-ergic activity does indeed increase food intake. In these studies, exogenous NPY,[19] an NPY agonist such as dexamethasone[20] or N-acetyl [Leu 28, Leu31] NPY (24-36)[21] are injected into the third ventricle[19] or at the level of the hypothalamus with a cannula.[20][22]

Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY agonists increases food intake compared to baseline data in rats. The effects of NPYergic activity on food intake is also demonstrated by the blockade of certain NPY receptors (Y1 and Y5 receptors), which, as was expected, inhibited NPYergic activity; thus, decreases food intake. However, a 1999 study by King et al. demonstrated the effects of the activation of the NPY autoreceptor Y2, which has been shown to inhibit the release of NPY and thus acts to regulate food intake upon its activation.[23] In this study a highly selective Y2 antagonist, BIIE0246 was administered locally into the ARC. Radioimmunoassay data, following the injection of BIIE0246, shows a significant increase in NPY release compared to the control group. Though the pharmacological half-life of exogenous NPY, other agonists, and antagonist is still obscure, the effects are not long lasting and the rat body employs an excellent ability to regulate and normalize abnormal NPY levels and therefore food consumption.[19]

## Connection to obesity

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A study in genetically obese rats to demonstrated the role of NPY in eating disorders such as obesity. Four underlying factors that contribute to obesity in rats are:

* an increase in glucocorticosteroid concentrations in plasma;
* insensitivity or resistance to insulin;
* mutation of leptin receptor; and
* an increase in NPY mRNA and NPY release.[24]

In obesity chronically elevated levels of NPY can be seen, this has been seen in rats fed on a high fat diet for 22 weeks and resulted in a genetic mutation increasing NPY release due to a defective leptin signal compared to control rats. In humans increased levels of free NPY were found in obese women and not in their leaner counterparts, analysing human hypothalamus' for NYP concentration however is more difficult than rats.[25] During weaning in rats there is an early expression of gene mutations that increase hypothalamic release of NPY in rats, however in humans multiple genes are commonly associated with the results of obesity and metabolic syndrome.[25] In most obesity cases the increased secretion of NPY is a central / hypothalamic resistance to energy excess hormone signals such as leptin, that can be a result of a variety of reasons in the CNS. In rodents resistant to obesity when fed on an obesogenic diet they had a significantly lower amount of NPY receptor in the hypothalamus suggesting an increased activity of NPY neurons in obese rats meaning that the reduction in the release of NPY may be beneficial to the reduction of obesity incidence alongside the consumption of a healthy diet and exercise. This would need to be seen in human research before looking at this avenue of weight loss although currently there is some evidence that suggests NPY is a significant predictor in weight regain after weight loss to maintain old levels of energy storage.[25]

Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate gluconeogenesis, which subsequently causes an increase of blood glucose that activates the release of insulin to regulate glucose levels by causing its reuptake and storage as glycogen in the tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, insulin resistance prevents high blood glucose regulation, resulting in morbid levels of glucose and diabetes mellitus.[26] In addition, high levels of glucocorticosteroids causes an increase of NPY by directly activating type II glucocorticosteroids receptors (which are activated only by relatively high levels of glucocorticosteroids) and, indirectly, by abolishing the negative feedback of corticotropin-releasing factor (CRF) on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the leptin receptor (ObRb) results in the abolition of inhibition of NPYergic activity and ultimately food intake via other negative feedback mechanisms to regulate them. Obesity in rats was significantly reduced by adrenalectomy[27] or hypophysectomy.[28]

## Clinical significance

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### Alcoholism

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The role of Neuropeptide Y has gained substantial attention for its involvement with alcoholism due to its the diverse range of physiological effects. NPY neurons have been shown to interact with dopaminergic reward and emotion pathways in the nucleus accumbens and amygdala, respectively. NPY expression levels and alcohol preference have been shown exhibit an inverse relationship. Expression levels are dependent on the brain area of interest. This indicates that baseline NPY levels could possibly influence innate alcohol preferences.[3]

Previous studies have identified NPY's anxiolytic effects to a possible therapeutic drug target for alcoholism.[29] As stated before, NPY levels and ethanol intake show an inverse relationship, therefore, increasing NPY availability could decrease alcohol intake. By creating a chemical antagonist for a Y2 receptor that would indirectly act as an agonist and stimulate Y1 receptors, alcohol consumption was successfully decreased in rats.[30] Additionally, another similar study identified that NPY expression may be connected to behavioral regulation in relation to alcohol dependence. Administration of neuropeptide Y was found to reduce binge-drinking behavior.[31] Although, it has been shown that NPY gene expression, mRNA or neuropeptide levels are not influenced by long-term alcohol consumption, but changes do occur during withdrawal from alcohol. These findings show that Neuropeptide Y has varying effects on alcohol consumption.[30]

Two results suggest that NPY might protect against alcoholism:

* knock-out mice in which a type of NPY receptor has been removed show a higher voluntary intake of alcohol and a higher resistance to alcohol's sedating effects, compared to normal mice;[32]
* the common fruit fly has a neuropeptide that is similar to NPY, known as neuropeptide F. The levels of neuropeptide F are lowered in sexually frustrated male flies, and this causes the flies to increase their voluntary intake of alcohol.[33]

### Stress and anxiety

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Neuropeptide Y is considered to be an anxiolytic endogenous peptide and its levels can be modulated by stress. NPY has connections to the HPA axis and is believed to be necessary for stress modulation.[34] It has been shown that higher levels of the Y1 and Y5 receptors in the amygdala result in reduced level of anxiety.[35] Additionally, the Y1 receptor has been linked to anxiolytic effects in the forebrain while Y2 has been associated with the pons.[7]

Conversely, higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder[36] and with dampening the fear response, allowing individuals to perform better under extreme stress.[37]

Studies of mice and monkeys show that repeated stress—and a high-fat, high-sugar diet—stimulate the release of neuropeptide Y, causing fat to build up in the abdomen. Researchers believe that by manipulating levels of NPY, they could eliminate fat from areas where it was not desired and accumulate at sites where it is needed.[5][38]

## See also

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* Anorexia nervosa
* Antianalgesia
* Neuropeptide
* Obesity

## References

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1. ↑ Heilig M, Widerlöv E (1995). "Neurobiology and clinical aspects of neuropeptide Y". Critical Reviews in Neurobiology. 9 (2–3): 115–36. PMID 8581979.
2. ↑ 2.0 2.1 Decressac M, Barker RA (December 2012). "Neuropeptide Y and its role in CNS disease and repair". Experimental Neurology. 238 (2): 265–72. doi:10.1016/j.expneurol.2012.09.004. PMID 23022456.
3. ↑ 3.0 3.1 3.2 Robinson SL, Thiele TE (2017). "The Role of Neuropeptide Y (NPY) in Alcohol and Drug Abuse Disorders". International Review of Neurobiology. 136: 177–197. doi:10.1016/bs.irn.2017.06.005. PMID 29056151.
4. ↑ 4.0 4.1 4.2 Tatemoto K (2004). "Neuropeptide Y: History and Overview". In Michel MC. Handbook of Experimental Pharmacology. 162. Springer. pp. 2–15.
5. ↑ 5.0 5.1 Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z (July 2007). "Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome". Nature Medicine. 13 (7): 803–11. doi:10.1038/nm1611. PMID 17603492.
6. ↑ Colmers WF, El Bahh B (March 2003). "Neuropeptide Y and Epilepsy". Epilepsy Currents. 3 (2): 53–58. doi:10.1046/j.1535-7597.2003.03208.x. PMC 321170. PMID 15309085.
7. ↑ 7.0 7.1 Kask A, Harro J, von Hörsten S, Redrobe JP, Dumont Y, Quirion R (May 2002). "The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y". Neuroscience and Biobehavioral Reviews. 26 (3): 259–83. doi:10.1016/s0149-7634(01)00066-5. PMID 12034130.
8. ↑ Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T (March 1998). "XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors". Pharmacological Reviews. 50 (1): 143–50. PMID 9549761.
9. ↑ Acuna-Goycolea C, Tamamaki N, Yanagawa Y, Obata K, van den Pol AN (August 2005). "Mechanisms of neuropeptide Y, peptide YY, and pancreatic polypeptide inhibition of identified green fluorescent protein-expressing GABA neurons in the hypothalamic neuroendocrine arcuate nucleus". The Journal of Neuroscience. 25 (32): 7406–19. doi:10.1523/jneurosci.1008-05.2005. PMID 16093392.
10. ↑ Kautz M, Charney DS, Murrough JW (May 2017). "Neuropeptide Y, resilience, and PTSD therapeutics". Neuroscience Letters. 649: 164–169. doi:10.1016/j.neulet.2016.11.061. PMID 27913193.
11. ↑ 11.0 11.1 Decressac M, Wright B, David B, Tyers P, Jaber M, Barker RA, Gaillard A (March 2011). "Exogenous neuropeptide Y promotes in vivo hippocampal neurogenesis". Hippocampus. 21 (3): 233–8. doi:10.1002/hipo.20765. PMID 20095007.
12. ↑ Howell OW, Doyle K, Goodman JH, Scharfman HE, Herzog H, Pringle A, Beck-Sickinger AG, Gray WP (May 2005). "Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus". Journal of Neurochemistry. 93 (3): 560–70. doi:10.1111/j.1471-4159.2005.03057.x. PMID 15836615.
13. ↑ Malva JO, Xapelli S, Baptista S, Valero J, Agasse F, Ferreira R, Silva AP (December 2012). "Multifaces of neuropeptide Y in the brain--neuroprotection, neurogenesis and neuroinflammation". Neuropeptides. 46 (6): 299–308. doi:10.1016/j.npep.2012.09.001. PMID 23116540.
14. ↑ Hansel DE, Eipper BA, Ronnett GV (April 2001). "Neuropeptide Y functions as a neuroproliferative factor". Nature. 410 (6831): 940–4. doi:10.1038/35073601. PMID 11309620.
15. ↑ Allen YS, Adrian TE, Allen JM, Tatemoto K, Crow TJ, Bloom SR, Polak JM (August 1983). "Neuropeptide Y distribution in the rat brain". Science. 221 (4613): 877–9. doi:10.1126/science.6136091. PMID 6136091.
16. ↑ Morris BJ (December 1989). "Neuronal localisation of neuropeptide Y gene expression in rat brain". The Journal of Comparative Neurology. 290 (3): 358–68. doi:10.1002/cne.902900305. PMID 2592617.
17. ↑ Haas DA, George SR (October 1989). "Neuropeptide Y-induced effects on hypothalamic corticotropin-releasing factor content and release are dependent on noradrenergic/adrenergic neurotransmission". Brain Research. 498 (2): 333–8. doi:10.1016/0006-8993(89)91112-8. PMID 2551461.
18. ↑ Edwardson JA, Hough CA (April 1975). "The pituitary-adrenal system of the genetically obese (ob/ob) mouse". The Journal of Endocrinology. 65 (1): 99–107. doi:10.1677/joe.0.0650099. PMID 167093.
19. ↑ 19.0 19.1 19.2 Hanson ES, Dallman MF (April 1995). "Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis". Journal of Neuroendocrinology. 7 (4): 273–9. doi:10.1111/j.1365-2826.1995.tb00757.x. PMID 7647769.
20. ↑ 20.0 20.1 White BD, Dean RG, Edwards GL, Martin RJ (May 1994). "Type II corticosteroid receptor stimulation increases NPY gene expression in basomedial hypothalamus of rats". The American Journal of Physiology. 266 (5 Pt 2): R1523–9. PMID 8203629.
21. ↑ King PJ, Widdowson PS, Doods HN, Williams G (August 1999). "Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices". Journal of Neurochemistry. 73 (2): 641–6. doi:10.1046/j.1471-4159.1999.0730641.x. PMID 10428060.
22. ↑ Pomonis JD, Levine AS, Billington CJ (July 1997). "Interaction of the hypothalamic paraventricular nucleus and central nucleus of the amygdala in naloxone blockade of neuropeptide Y-induced feeding revealed by c-fos expression". The Journal of Neuroscience. 17 (13): 5175–82. PMID 9185555.
23. ↑ King PJ, Williams G, Doods H, Widdowson PS (May 2000). "Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release". European Journal of Pharmacology. 396 (1): R1–3. doi:10.1016/S0014-2999(00)00230-2. PMID 10822055.
24. ↑ Dryden S, Pickavance L, Frankish HM, Williams G (September 1995). "Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats". Brain Research. 690 (2): 185–8. doi:10.1016/0006-8993(95)00628-4. PMID 8535835.
25. ↑ 25.0 25.1 25.2 Minor RK, Chang JW, de Cabo R (February 2009). "Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction". Molecular and Cellular Endocrinology. 299 (1): 79–88. doi:10.1016/j.mce.2008.10.044. PMC 2668104. PMID 19041366.
26. ↑ Wilcox G (May 2005). "Insulin and insulin resistance". The Clinical Biochemist. Reviews. 26 (2): 19–39. PMC 1204764. PMID 16278749.
27. ↑ Yukimura Y, Bray GA (1978). "Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker (fatty) rat". Endocrine Research Communications. 5 (3): 189–98. doi:10.1080/07435807809083752. PMID 747998.
28. ↑ Powley TL, Morton SA (April 1976). "Hypophysectomy and regulation of body weight in the genetically obese Zucker rat". The American Journal of Physiology. 230 (4): 982–7. doi:10.1152/ajplegacy.1976.230.4.982. PMID 1267030.
29. ↑ Thorsell A, Mathé AA (2017). "Neuropeptide Y in Alcohol Addiction and Affective Disorders". Frontiers in Endocrinology. 8: 178. doi:10.3389/fendo.2017.00178. PMC 5534438. PMID 28824541.
30. ↑ 30.0 30.1 Ciccocioppo R, Gehlert DR, Ryabinin A, Kaur S, Cippitelli A, Thorsell A, et al. (November 2009). "Stress-related neuropeptides and alcoholism: CRH, NPY, and beyond". Alcohol. 43 (7): 491–8. doi:10.1016/j.alcohol.2009.08.003. PMC 2804869. PMID 19913192.
31. ↑ Sparrow AM, Lowery-Gionta EG, Pleil KE, Li C, Sprow GM, Cox BR, Rinker JA, Jijon AM, Peňa J, Navarro M, Kash TL, Thiele TE (May 2012). "Central neuropeptide Y modulates binge-like ethanol drinking in C57BL/6J mice via Y1 and Y2 receptors". Neuropsychopharmacology. 37 (6): 1409–21. doi:10.1038/npp.2011.327. PMC 3327846. PMID 22218088.
32. ↑ Thiele TE, Koh MT, Pedrazzini T (February 2002). "Voluntary alcohol consumption is controlled via the neuropeptide Y Y1 receptor". The Journal of Neuroscience. 22 (3): RC208. PMID 11826154.
33. ↑ "Deprived of Sex, Jilted Flies Drink More Alcohol". UCSF News Center. March 15, 2012.
34. ↑ Reichmann F, Holzer P (February 2016). "Neuropeptide Y: A stressful review". Neuropeptides. 55: 99–109. doi:10.1016/j.npep.2015.09.008. PMC 4830398. PMID 26441327.
35. ↑ Dumont Y, Quirion R (December 2014). "Neuropeptide Y pathways in anxiety-related disorders". Biological Psychiatry. 76 (11): 834–5. doi:10.1016/j.biopsych.2014.09.015. PMID 25439997.
36. ↑ Yehuda R, Brand S, Yang RK (April 2006). "Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping". Biological Psychiatry. 59 (7): 660–3. doi:10.1016/j.biopsych.2005.08.027. PMID 16325152.
37. ↑ Julie Steenhuysen (February 16, 2009). "Research shows why some soldiers are cool under fire".
38. ↑ Maugh TH (July 2, 2007). "Research points to way to eliminate belly fat". Chicago Tribune.

## External links

[edit | edit source]

* EMBL receptor database entry
* Neuropeptide Y at the US National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

PDB gallery

* 1f8p: PORCINE NEUROPEPTIDE Y BOUND TO DPC MICELLES

1f8p: PORCINE NEUROPEPTIDE Y BOUND TO DPC MICELLES

* 1fvn: [ALA31, AIB32]-NEUROPEPTIDE Y

1fvn: [ALA31, AIB32]-NEUROPEPTIDE Y

* 1icy: [ALA31,PRO32]-PNPY BOUND TO DPC MICELLES

1icy: [ALA31,PRO32]-PNPY BOUND TO DPC MICELLES

* 1ron: NMR SOLUTION STRUCTURE OF HUMAN NEUROPEPTIDE Y

1ron: NMR SOLUTION STRUCTURE OF HUMAN NEUROPEPTIDE Y

* v
* t
* e

Peptides: neuropeptides

Hormones|

see hormones

Opioid peptides|

| Dynorphins|

* Dynorphin A
* Dynorphin A1–8
* Dynorphin B
* Big dynorphin
* Leumorphin
* α-Neoendorphin
* β-Neoendorphin

|

Endomorphins|

* Endomorphin-1
* Endomorphin-2

Endorphins|

* α-Endorphin
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Enkephalins|

* Met-enkephalin
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Others|

* Adrenorphin
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Other
neuropeptides|

| Kinins|

Bradykinins
Tachykinins: mammal

* Substance P
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amphibian

* Kassinin
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|

Neuromedins|

* B
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* U

Orexins|

* A
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Other|

* Angiotensin
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* Neurophysins
* Neurotensin
* Pancreatic polypeptide
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* RVD-Hpα
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Appetite stimulants (A15)

Exogenous|

* Amitriptyline
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Endogenous|

* ACTH/Corticotropin
* Adiponectin
* Agouti-related peptide
* Anandamide
* Cortisol/Hydrocortisone
* Cortisone
* Ghrelin
* Melanin-concentrating hormone
* Melatonin
* Neuropeptide Y
* Orexin/Hypocretin

* v
* t
* e

Signaling peptide/protein receptor modulators

Adiponectin|

| AdipoR1|

* Agonists: Peptide: Adiponectin
* ADP-355
* ADP-399; Non-peptide: AdipoRon
* (–)-Arctigenin
* Arctiin
* Gramine
* Matairesinol

* Antagonists: Peptide: ADP-400

|

AdipoR2|

* Agonists: Peptide: Adiponectin
* ADP-355
* ADP-399; Non-peptide: AdipoRon
* Deoxyschizandrin
* Parthenolide
* Syringing
* Taxifoliol

* Antagonists: Peptide: ADP-400

Angiotensin|

* See here instead.

Bradykinin|

* Agonists: Bradykinin
* Kallidin

* Antagonists: FR-173657
* Icatibant
* LF22-0542

CGRP|

* Agonists: Amylin
* CGRP
* Pramlintide

* Antagonists: Atogepant
* BI 44370 TA
* CGRP (8-37)
* MK-3207
* Olcegepant
* Rimegepant
* SB-268262
* Telcagepant
* Ubrogepant

* Antibodies: Eptinezumab
* Erenumab
* Fremanezumab
* Galcanezumab

Cholecystokinin|

| CCKA|

* Agonists: Cholecystokinin

* Antagonists: Amiglumide
* Asperlicin
* Devazepide
* Dexloxiglumide
* Lintitript
* Lorglumide
* Loxiglumide
* Pranazepide
* Proglumide
* Tarazepide
* Tomoglumide

|

CCKB|

* Agonists: Cholecystokinin
* CCK-4
* Gastrin
* Pentagastrin (CCK-5)

* Antagonists: Ceclazepide
* CI-988 (PD-134308)
* Itriglumide
* L-365,360
* Netazepide
* Proglumide
* Spiroglumide

Unsorted|

* Antagonists: Nastorazepide

CRH|

| CRF1|

* Agonists: Cortagine
* Corticorelin
* Corticotropin releasing hormone
* Sauvagine
* Stressin I
* Urocortin

* Antagonists: Antalarmin
* Astressin-B
* CP-154,526
* Emicerfont
* Hypericin
* LWH-234
* NBI-27914
* NBI-74788
* Pexacerfont
* R-121919
* TS-041
* Verucerfont

|

CRF2|

* Agonists: Corticorelin
* Corticotropin releasing hormone
* Sauvagine
* Urocortin

* Antagonists: Astressin-B

Cytokine|

See here instead.

Endothelin|

* Agonists: Endothelin 1
* Endothelin 2
* Endothelin 3
* IRL-1620

* Antagonists: A-192621
* ACT-132577
* Ambrisentan
* Aprocitentan
* Atrasentan
* Avosentan
* Bosentan
* BQ-123
* BQ-788
* Clazosentan
* Darusentan
* Edonentan
* Enrasentan
* Fandosentan
* Feloprentan
* Macitentan
* Nebentan
* Sitaxentan
* Sparsentan
* Tezosentan
* Zibotentan

Galanin|

| GAL1|

* Agonists: Galanin
* Galanin (1-15)
* Galanin-like peptide
* Galmic
* Galnon
* NAX 810-2

* Antagonists: C7
* Dithiepine-1,1,4,4-tetroxide
* Galantide (M15)
* M32
* M35
* M40
* SCH-202596

|

GAL2|

* Agonists: Galanin
* Galanin (1-15)
* Galanin (2-11)
* Galanin-like peptide
* Galmic
* Galnon
* J18
* NAX 810-2

* Antagonists: C7
* Galantide (M15)
* M32
* M35
* M40
* M871

GAL3|

* Agonists: Galanin
* Galanin (1-15)
* Galmic
* Galnon

* Antagonists: C7
* Galantide (M15)
* GalR3ant
* HT-2157
* M32
* M35
* M40
* SNAP-37889
* SNAP-398299

Ghrelin/GHS|

* See here instead.

GH|

* See here instead.

GHRH|

* See here instead.

GLP|

| GLP-1|

* Agonists: Albiglutide
* Beinaglutide
* Dulaglutide
* Efpeglenatide
* Exenatide
* GLP-1
* Langlenatide
* Liraglutide
* Lixisenatide
* Oxyntomodulin
* Pegapamodutide
* Semaglutide
* Taspoglutide

|

GLP-2|

* Agonists: Apraglutide
* Elsiglutide
* Glepaglutide
* GLP-2
* Teduglutide

Others|

* Propeptides: Preproglucagon
* Proglucagon

Glucagon|

* Agonists: Dasiglucagon
* Glucagon
* Oxyntomodulin

* Antagonists: Adomeglivant
* L-168,049
* LGD-6972

* Propeptides: Preproglucagon
* Proglucagon

GnRH|

* See here instead.

Gonadotropin|

* See here instead.

Growth factor|

See here instead.

Insulin|

* Agonists: Chaetochromin (4548-G05)
* Insulin-like growth factor 1
* Insulin-like growth factor 2
* Insulin
* Insulin aspart
* Insulin degludec
* Insulin detemir
* Insulin glargine
* Insulin glulisine
* Insulin lispro
* Mecasermin
* Mecasermin rinfabate

* Antagonists: BMS-754807
* S661
* S961

* Kinase inhibitors: Linsitinib

* Antibodies: Xentuzumab (against IGF-1 and IGF-2)

Kisspeptin|

* Agonists: Kisspeptin
* Kisspeptin-10

* Antagonists: Kisspeptin-234

Leptin|

* Agonists: Leptin
* Metreleptin

MCH|

| MCH1|

* Agonists: Melanin concentrating hormone

* Antagonists: ATC-0065
* ATC-0175
* GW-803430
* NGD-4715
* SNAP-7941
* SNAP-94847

|

MCH2|

* Agonists: Melanin concentrating hormone

Melanocortin|

* See here instead.

Neuropeptide FF|

* Agonists: Neuropeptide AF
* Neuropeptide FF
* Neuropeptide SF (RFRP-1)
* Neuropeptide VF (RFRP-3)

* Antagonists: BIBP-3226
* RF9

Neuropeptide S|

* Agonists: Neuropeptide S

* Antagonists: ML-154
* SHA-68

Neuropeptide Y|

| Y1|

* Agonists: Neuropeptide Y
* Peptide YY

* Antagonists: BIBO-3304
* BIBP-3226
* BVD-10
* GR-231118
* PD-160170

|

Y2|

* Agonists: 2-Thiouridine 5'-triphosphate
* Neuropeptide Y
* Neuropeptide Y (13-36)
* Peptide YY
* Peptide YY (3-36)

* Antagonists: BIIE-0246
* JNJ-5207787
* SF-11

Y4|

* Agonists: GR-231118
* Neuropeptide Y
* Pancreatic polypeptide
* Peptide YY

* Antagonists: UR-AK49

Y5|

* Agonists: BWX-46
* Neuropeptide Y
* Peptide YY

* Antagonists: CGP-71683
* FMS-586
* L-152,804
* Lu AA-33810
* MK-0557
* NTNCB
* Velneperit (S-2367)

Neurotensin|

| NTS1|

* Agonists: Neurotensin
* Neuromedin N

* Antagonists: Meclinertant
* SR-142948

|

NTS2|

* Agonists: Neurotensin

* Antagonists: Levocabastine
* SR-142948

Opioid|

See here instead.

Orexin|

| OX1|

* Agonists: Orexin (A, B)

* Antagonists: ACT-335827
* ACT-462206
* Almorexant
* Filorexant
* Lemborexant
* Nemorexant
* RTIOX-276
* SB-334867
* SB-408124
* SB-649868
* Suvorexant
* TCS-1102

|

OX2|

* Agonists: Orexin (A, B)
* SB-668875

* Antagonists: ACT-335827
* ACT-462206
* Almorexant
* EMPA
* Filorexant
* JNJ-10397049
* Lemborexant
* MK-1064
* SB-649868
* Seltorexant
* Suvorexant
* TCS-1102
* TCS-OX2-29

Oxytocin|

* See here instead.

Prolactin|

* Agonists: Growth hormone
* Human placental lactogen
* Placental growth hormone (growth hormone variant)
* Prolactin
* S179D-hPRL
* Somatotropin

* Antagonists: Δ1–9-G129R-hPRL
* Δ1–14-G129R-hPRL
* G120K-hGH
* G129R-hPRL

* Prolactin modulators: Prolactin inhibitors: D2 receptor agonists (e.g., bromocriptine, cabergoline); Prolactin releasers: D2 receptor antagonists (e.g., domperidone, metoclopramide, risperidone)
* Estrogens (e.g., estradiol)
* Progestogens (e.g., progesterone)

PTH|

* Agonists: Abaloparatide
* Parathyroid hormone
* Parathyroid hormone-related protein (PTHrP)
* Semparatide
* Teriparatide

Relaxin|

* Agonists: Insulin-like factor 3
* Relaxin (1, 2, 3)
* Serelaxin

Somatostatin|

* See here instead.

Tachykinin|

* See here instead.

TRH|

* Agonists: Azetirelin
* Fertirelin
* Montirelin
* Orotirelin
* Posatirelin
* Protirelin
* Rovatirelin
* Taltirelin
* TRH (TRF)

TSH|

* Agonists: Thyrotropin alfa
* TSH (thyrotropin)

Vasopressin|

* See here instead.

VIP/PACAP|

| VIPR1|

* Agonists: Peptide: Bay 55-9837
* LBT-3393
* PACAP
* VIP

|

VIPR2|

* Agonists: Peptide: LBT-3627
* PACAP
* VIP

PAC1|

* Agonists: PACAP
* PACAP (1-27)
* PACAP (1-38)

* Antagonists: PACAP (6-38)

Unsorted|

* PHI
* PHM
* PHV

Others|

* Endogenous: Adrenomedullin
* Apelin
* Asprosin
* Bombesin
* Calcitonin
* Carnosine
* CART
* CLIP
* DSIP
* Enteroglucagon
* Formyl peptide
* GALP
* GIP
* GRP
* Integrin ligands (collagens, fibrinogen, fibronectin, laminins, ICAM-1, ICAM-2, osteopontin, VCAM-1, vitronectin)
* Kininogens
* Motilin
* Natriuretic peptides (ANP, BNP, CNP, urodilatin)
* Nesfatin-1
* Neuromedin B
* Neuromedin N
* Neuromedin S
* Neuromedin U
* Obestatin
* Osteocalcin
* Resistin
* Secretin
* Thymopoietin
* Thymosins
* Thymulin
* Urotensin-II
* VGF

* Exogenous: Lifitegrast (LFA-1 antagonist)

See also
Receptor/signaling modulators

* v
* t
* e

Sigma receptor modulators

σ1|

* Agonists: 3-PPP
* 4-PPBP
* 5-MeO-DMT
* Alazocine (SKF-10047)
* Amantadine
* ANAVEX2-73
* Arketamine
* BD-737
* BD-1052
* Captodiame
* Citalopram
* CGRP
* Cloperastine
* Cocaine
* Cutamesine (SA-4503)
* Cyclazocine
* Dehydroepiandrosterone (DHEA) (prasterone)
* Dehydroepiandrosterone sulfate (DHEA-S) (prasterone sulfate)
* Dextrallorphan
* Dextromethorphan (DXM)
* Dextrorphan (DXO)
* Dimemorfan
* Dimethyltryptamine (DMT)
* Ditolylguanidine (DTG)
* Donepezil
* Eliprodil
* Escitalopram
* Fabomotizole (afobazole)
* Fluoxetine
* Fluvoxamine
* Ifenprodil
* Igmesine (JO-1784)
* IPAB
* Ketamine
* L-687384
* MDMA (midomafetamine)
* Memantine
* Methamphetamine
* Methoxetamine
* Methylphenidate
* Nepinalone
* Neuropeptide Y
* Noscapine
* OPC-14523
* Opipramol
* Pentazocine
* Pentoxyverine (carbetapentane)
* PRE-084
* Pregnenolone
* Pregnenolone sulfate
* Pridopidine
* Racemethorphan (methorphan)
* Racemorphan (morphanol)
* UMB-23
* UMB-82

* Antagonists: 3-PPP
* AC-927
* BD-1008
* BD-1031
* BD-1047
* BD-1060
* BD-1063
* BD-1067
* BMY-14802 (BMS-181100)
* CM-156
* Dup-734
* E-5842
* E-52862 (S1RA)
* Haloperidol
* LR-132
* LR-172
* MS-377
* NE-100
* NPC-16377
* Panamesine (EMD-57455)
* PD-144418
* Pentazocine
* Progesterone
* Rimcazole (BW-234U)
* Sertraline
* SR-31742A

* Allosteric modulators: Phenytoin; Positive: Methylphenylpiracetam
* SOMCL-668

* Unknown/unsorted: 3-Methoxydextrallorphan
* 3-MeO-PCP
* 4C-T-2
* 4-IBP
* 4-IPBS
* 4-MeO-PCP
* 5-MeO-DALT
* 5-MeO-DiPT
* Amitriptyline
* Azidopamil
* Chlorpromazine
* Clemastine
* Clomipramine
* Clorgiline
* D-Deprenyl
* DiPT
* DPT
* Ibogaine
* Imipramine
* KCR-12-83.1
* Nemonapride
* Noribogaine
* RHL-033
* RS-67,333
* RTI-55
* Saffron
* Safinamide
* Selegiline
* Spipethiane
* Trifluoperazine
* W-18
* YKP10A

σ2|

* Agonists: 3-PPP
* Arketamine
* BD-1047
* BD1063
* Ditolylguanidine (DTG)
* DKR-1005
* DKR-1051
* Haloperidol
* Ifenprodil
* Ketamine
* MDMA (midomafetamine)
* Methamphetamine
* OPC-14523
* Opipramol
* PB-28
* Phencyclidine
* Siramesine (Lu 28-179)
* UKH-1114

* Antagonists: AC-927
* BD-1008
* BD-1067
* CM-156
* CT-1812
* LR-172
* MIN-101
* Panamesine (EMD-57455)
* SAS-0132

* Unknown/unsorted: 3-Methoxydextrallorphan
* 3-MeO-PCE
* 4-MeO-PCP
* 5-MeO-DALT
* 5-MeO-DiPT
* Clemastine
* DiPT
* DPT
* Ibogaine
* Nemonapride
* Nepinalone
* Noribogaine
* Pentazocine
* RS-67,333
* Safinamide
* TMA
* UMB-23
* UMB-82
* W-18

Unsorted|

* Agonists: Berberine
* Ethylketazocine
* Fourphit
* Metaphit
* Naluzotan
* Tapentadol
* Tenocyclidine

* Antagonists: AHD1
* AZ66
* Lamotrigine
* Naloxone
* SM-21
* UMB-100
* UMB-101
* UMB-103
* UMB-116
* YZ-011
* YZ-069
* YZ-185

* Allosteric modulators: SKF-83959

* Unknown/unsorted: 18-Methoxycoronaridine
* BMY-13980
* Butaclamol
* Caramiphen
* Carvotroline
* Chlorphenamine (chlorpheniramine)
* Chlorpromazine
* Cinnarizine
* Cinuperone
* Clocapramine
* Dezocine
* EMD-59983
* Hypericin (St. John's wort)
* Fluphenazine
* Gevotroline (WY-47384)
* Mepyramine (pyrilamine)
* Molindone
* Perphenazine
* Pimozide
* Proadifen
* Promethazine
* Propranolol
* Quinidine
* Remoxipride
* SL 82.0715
* SR-31747A
* Tiospirone (BMY-13859)
* Venlafaxine

See also: Receptor/signaling modulators
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[CGRP]: Calcitonin gene-related peptide
*[MDMA]: Methylenedioxymethamphetamine
*[DiPT]: N,N-Diisopropyltryptamine
*[DPT]: N,N-Dipropyltryptamine
*[TMA]: 3,4,5-Trimethoxyamphetamine