September 2021

Bremelanotide is a 7 amino acid (AA) analogue of α melanocyte-stimulating hormone (α-MSH) used in scientific research studies as a treatment for hyposexual sexual desire disorder (HSDD) in women¹. As a peptide, bremelanotide is injected subcutaneously, although intranasal administration has shown efficacy in stimulating sexual arousal in female vitro test subjects. Male vitro test subjects with sexual dysfunction also demonstrate increased sexual arousal and erectile responses after subcutaneous bremelanotide injection, including subjects for whom Viagra was ineffective³. In addition to its beneficial role in sexual dysfunction studies, bremelanotide has excellent utility in many different fields of neuroscience research. DISCLAIMER: All products from Blue Sky Peptide are for laboratory research only and are not suitable for human consumption. Any other use violates the terms and conditions for purchase. Bremelanotide should only be used in carefully controlled laboratory conditions with appropriate personal protective equipment. If exposure occurs, immediately rinse the affected area and seek medical help if symptoms present. Bremelanotide is a melanocortin receptor (MCR) agonist that preferentially interacts with the melanocortin receptor subtype 4 (MC4R)⁴. The melanocortins and their receptors were first identified as pituitary factors involved in skin darkening in frogs. Eventually, however, the exploration of the melanocortin system extended to mammalian systems⁵. The melanocortin system contributes to skin pigmentation, inflammation, appetite, memory, and sexual behavior^5-8. The different MCR subtypes play distinct roles and are differentially expressed across the body. Melanocortins, also known as melanocyte-stimulating hormones (MSH), are all small peptide hormones derived from proopiomelanocortin and serve as the primary agonists of MCRs along with adrenocorticotropic hormone (ACTH)⁹. MSH peptides come in 3 types: α-MSH, β-MSH, γ-MSH. MC4R is primarily localized in the brain and is considered a neural MCR¹⁰. One of the primary roles of MC4R is regulating food intake by mediating the effects of leptin¹¹. Administering α-MSH reduces feeding in obese rats, especially when applied directly to the paraventricular nucleus of the hypothalamus (PVN), a critical autonomic control center of the brain involved with stress responses, growth, and reproduction^12-14. In addition to food intake, MC4R plays a role in other processes like glucose and lipid homeostasis, disease-associated lean body mass wasting, and cardiovascular function¹⁰. Reproductive behavior is also intrinsically tied to MC4R and its ligands. Mice with reduced or absent MC4R function exhibit several sexual dysfunctions^15-17. Administration of MC4R agonist reversed these effects in some studies and caused erections and ejaculations in some animal models after central nervous system administration^10,18. Considering the breadth of life-essential roles the melanocortin system has, an MC4R-specific agonist like bremelanocortin is valuable for many lines of neuroscience research. In addition, bremelanocortin is extensively characterized in the literature and is well-tolerated by many species, including rats and humans. Therefore, bremelanocortin is, and has been, a powerful research tool. References:

1. Mayer D, Lynch SE. Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder. Ann Pharmacother. 2020;54(7):684-690.
2. Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Womens Health (Lond). 2016;12(3):325-337.
3. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res. 2004;16(2):135-142.
4. Pfaus JG, Sadiq A, Spana C, Clayton AH. The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women. CNS Spectr. 2021:1-9.
5. Wikberg JE, Muceniece R, Mandrika I, et al. New aspects on the melanocortins and their receptors. Pharmacol Res. 2000;42(5):393-420.
6. Shen Y, Fu WY, Cheng EY, Fu AK, Ip NY. Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism. J Neurosci. 2013;33(2):464-472.
7. Catania A, Lonati C, Sordi A, Carlin A, Leonardi P, Gatti S. The melanocortin system in control of inflammation. ScientificWorldJournal. 2010;10:1840-1853.
8. Ellacott KL, Cone RD. The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Lond B Biol Sci. 2006;361(1471):1265-1274.
9. Gantz I, Fong TM. The melanocortin system. Am J Physiol Endocrinol Metab. 2003;284(3):E468-474.
10. Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev. 2010;31(4):506-543.
11. Kask A, Rago L, Wikberg JE, Schioth HB. Evidence for involvement of the melanocortin MC4 receptor in the effects of leptin on food intake and body weight. Eur J Pharmacol. 1998;360(1):15-19.
12. Ferguson AV, Latchford KJ, Samson WK. The paraventricular nucleus of the hypothalamus - a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets. 2008;12(6):717-727.
13. Hansen MJ, Ball MJ, Morris MJ. Enhanced inhibitory feeding response to alpha-melanocyte stimulating hormone in the diet-induced obese rat. Brain Res. 2001;892(1):130-137.
14. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994;8(10):1298-1308.
15. Sandrock M, Schulz A, Merkwitz C, Schoneberg T, Spanel-Borowski K, Ricken A. Reduction in corpora lutea number in obese melanocortin-4-receptor-deficient mice. Reprod Biol Endocrinol. 2009;7:24.
16. Irani BG, Xiang Z, Moore MC, Mandel RJ, Haskell-Luevano C. Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse. Biochem Biophys Res Commun. 2005;326(3):638-644.
17. Van der Ploeg LH, Martin WJ, Howard AD, et al. A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci U S A. 2002;99(17):11381-11386.

18.       Bertolini A, Tacchi R, Vergoni AV. Brain effects of melanocortins. Pharmacol Res. 2009;59(1):13-47.

Proteins and peptides are some of the most commonly used reagents in modern life sciences. From short-chain peptide receptor agonists to biotinylated-antibodies, peptide-based reagents play pivotal roles in every stage of research. The ubiquity of peptides has created a vibrant market for them and protein reagents with many suppliers at different levels. However, not all peptide suppliers are the same, and neither are their products. Therefore, the first step to ordering research peptides online is to identify whether a supplier’s products are of the exacting standards needed to conduct effective research. Bad reagents can ruin an experiment and potentially sink entire projects. More insidiously, research conducted with poorly tested components can get published and contribute to the growing reproducibility crisis in science¹. In recent decades, irreproducibility has been brought to the forefront in science, with journals like Nature publishing extensively on the topic^2,3. In 2015, one study estimated that up to 50% of preclinical research is irreplicable. This has cost approximately $28,000,000,000 in US dollars⁴. One key point made by some authors is that differences in reagents, especially protein products like antibodies, have made achieving reproducible results difficult. Therefore, identifying which protein and peptide products are validated is crucial. There are databases and websites in which antibodies from different manufacturers are listed and compared for efficacy, with links to studies that use them⁵. However, there is no such catalog or comparable resource for small peptide products⁶. This doesn’t mean that there is no way to be sure your peptide products are of the purity and quality you expect. Peptide products should undergo quality control analysis through multiple methods. These techniques include high-performance liquid chromatography (HPLC), mass spectrometry (MS), and nuclear magnetic resonance analysis (NMR)^7-9. A reputable supplier will have quality control reports available on their product pages for some or all of these. Therefore, when shopping for research peptides online, it is pivotal to find quality control reports. Another factor to consider when shopping for research peptides online is customer service and accountability. Research is not a simple endeavor. Along the course of a project, it is a given that some experiments will not work out. In some cases, this is caused by the reagent. Even high-grade products will not work when used outside of their working conditions. By having direct contact with a peptide supplier, a researcher can troubleshoot issues that arise with their research peptide products. Additionally, a good return policy helps avoid losses if the product is not up to standards or does not match the application. Finally, and perhaps most obviously, pricing is critical. Research funds aren’t unlimited, and materials are only one of many costs that an investigator or lab manager must account for. Many suppliers offer scaling pricing options and periodic special offers. Additionally, some retailers have rewards programs that encourage repeat business. When searching for research peptides online, Blue Sky Peptides offers affordable peptides that come with quality control reports. We have in-depth customer support and a generous return policy. In addition, our site has regular sales, BOGO offers, discount codes, and our BSP Rewards Program. Visit our website or contact us today to see if our research peptides will meet your research needs. References:

1. Williams M. Reagent Validation to Facilitate Experimental Reproducibility. Curr Protoc Pharmacol. 2018;81(1):e40.
2. Baker M. 1,500 scientists lift the lid on reproducibility. Nature. 2016;533(7604):452-454.
3. Begley CG, Ioannidis JP. Reproducibility in science: improving the standard for basic and preclinical research. Circ Res. 2015;116(1):116-126.
4. Freedman LP, Cockburn IM, Simcoe TS. The Economics of Reproducibility in Preclinical Research. PLoS Biol. 2015;13(6):e1002165.
5. Antibodypedia. https://www.antibodypedia.com/. Accessed August 28, 2021.
6. Vergote V, Burvenich C, Van de Wiele C, De Spiegeleer B. Quality specifications for peptide drugs: a regulatory-pharmaceutical approach. J Pept Sci. 2009;15(11):697-710.
7. Choules MP, Bisson J, Gao W, et al. Quality Control of Therapeutic Peptides by (1)H NMR HiFSA Sequencing. J Org Chem. 2019;84(6):3055-3073.
8. Stalmans S, Gevaert B, Verbeke F, et al. Quality control of cationic cell-penetrating peptides. J Pharm Biomed Anal. 2016;117:289-297.
9. Zeng K, Geerlof-Vidavisky I, Gucinski A, Jiang X, Boyne MT, 2nd. Liquid Chromatography-High Resolution Mass Spectrometry for Peptide Drug Quality Control. AAPS J. 2015;17(3):643-651.

Fragment 176-191 is a small peptide that comprises the last 15 amino acids (AAs) from the c-terminal end of growth hormone (hGH)¹. During childhood, hGH plays a critical role in growth regulation. However, in adulthood, hGH’s most well-known function is metabolic. Among other actions, hGH stimulates insulin-like growth factor-1 (IGF-1) production and release^2-4. In addition, the release of hGH from the anterior pituitary gland is stimulated by hypothalamic growth hormone-releasing hormone (GHRH)⁵. Fragment 176-191 and similar hGH fragments have powerful lipolytic and anti-lipogenic properties that have drawn researchers’ interest for decades^6,7. Early investigation showed that injecting rats with c-terminal fragments of hGH caused a temporary increase in blood glucose and a more persistent boost in plasma insulin. Interestingly, fragments that did not contain AAs 178-191 had no effect. This provided crucial early evidence suggesting a minimum required sequence for a peptide to be biologically active⁷. Later research found that both hGH and the slightly truncated fragment 177-191 could cause weight loss in mice by promoting lipolysis, although a previous report suggests that it inhibits lipogenesis instead^8,9. Additionally, this study indicated that this is because the peptide sequence can boost the production of beta-3 adrenergic receptors (ADRB3)⁸. Interestingly, it does not appear that fragment 177-191 acts on hGH receptors and, unlike hGH, does not stimulate cell proliferation⁶. These results add to the body of evidence suggesting that hGH may be a prohormone with differentially truncated forms that have their own effects^6,10. Finally, fragment 177-191 co-injected with hyaluronic acid (HA) reduced cartilage degeneration and the degree of motor disability in a rat osteoarthritis model¹¹. These results highlight the utility of fragment 176-191 and related peptides as valuable research tools. Although a phase 2B clinical trial investigating fragment 177-191 as a treatment for obesity stalled, hGH c-terminal fragments provide means to manipulate lipid metabolism in the lab without the interfering factors of IGF-1 signaling alterations or GH receptor^6,12. This specificity could one day help researchers uncover novel mechanisms and future therapies.  

1. Wade JD, Ng FM, Bornstein J, Pullin CO, Pearce JS. Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177--191. Acta Endocrinol (Copenh). 1982;101(1):10-14.
2. Brinkman JE, Tariq MA, Leavitt L, Sharma S. Physiology, Growth Hormone. In: StatPearls. Treasure Island (FL)2021.
3. Bidlingmaier M, Strasburger CJ. Growth hormone. Handb Exp Pharmacol. 2010(195):187-200.
4. Ayuk J, Sheppard MC. Growth hormone and its disorders. Postgrad Med J. 2006;82(963):24-30.
5. Vance ML. Growth-hormone-releasing hormone. Clin Chem. 1990;36(3):415-420.
6. Heffernan MA, Thorburn AW, Fam B, et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001;25(10):1442-1449.
7. Ng FM, Bornstein J. Hyperglycemic action of synthetic C-terminal fragments of human growth hormone. Am J Physiol. 1978;234(5):E521-526.
8. Heffernan M, Summers RJ, Thorburn A, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology. 2001;142(12):5182-5189.
9. Wu Z, Ng FM. Antilipogenic action of synthetic C-terminal sequence 177-191 of human growth hormone. Biochem Mol Biol Int. 1993;30(1):187-196.
10. Devesa J, Almenglo C, Devesa P. Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth? Clin Med Insights Endocrinol Diabetes. 2016;9:47-71.
11. Kwon DR, Park GY. Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Ann Clin Lab Sci. 2015;45(4):426-432.
12. Heike Stier EV, David Kenley. Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans. Journal of Endocrinology & Metabolism. 2013;3:7-15.

Research peptides are small chains of amino acids used in pure and applied biological research but not in the clinic. Although there is overlap in the definitions of both peptides and proteins, peptides are generally defined as a small chain of between 2 and 50 amino acids (AAs)¹. Peptides are further differentiated based on size. Single unbranched strands between 10-20 AAs are called polypeptides, and oligopeptides are greater than 20 AAs long^1,2. Proteins are larger macromolecules consisting of hundreds to thousands of AAs that display secondary, tertiary, and quarternary structures¹. Clinical and academic researchers have used research peptides to probe mechanisms underlying disease and as novel therapeutics. For example, one such study by Ahmed et al. investigated the effects of tatCN21 treatment in an animal model of global cerebral ischemia, the cessation or reduction of blood flow to the brain³. TatCN21 is a 21 AA peptide inhibitor of the protein calcium-calmodulin (CaM) dependent protein kinase IIα (CaMKIIα) that is attached to a “tat sequence,” which allows the peptide to be brought into the cell. Ahmed et al. found that treating rats with tatCN21 3 hours after GCI protected neurons against programmed cell death and reduced spatial memory deficits³. Another group investigated using a tat-conjugated peptide to block the interaction of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1)⁴. Nrf2 is an important transcription factor that activates the cellular antioxidation response and regulates signaling pathways in cancer and inflammation^5,6. Keap1 binds to Nrf2, preventing its activation and nuclear translocation ⁷. Steel et al. found that administering tat-conjugated peptide sequences that target this interaction could activate Nrf2 signaling and its downstream target genes in human THP-1 monocytes⁴. Many peptide hormones have been investigated for their potential beneficial properties in various diseases. Some of these, such as vasopressin, oxytocin, and insulin, have made it to the clinic, while others are in clinical trials⁸. Currently, 80 peptide medications are approved for medical use. However, bringing new peptides to market requires careful consideration of renal clearance and delivery methods to make sure the drugs make it to their target tissue^9,10. Research peptides have significantly advanced our understanding in health and disease. However, quality research requires peptides you can trust. Blue Sky Peptide sells the highest-grade research peptides on the market. In addition, we regularly offer BOGO deals, weekly promotions, and a rewards program that gives back when you shop with us. Check out our product catalog or contact us to see what Blue Sky Peptide can do for your research projects. All products from Blue Sky Peptide are for laboratory research only and are not suitable for human consumption. Any other use violates the terms and conditions for purchase. References:

1. Forbes J, Krishnamurthy K. Biochemistry, Peptide. In: StatPearls. Treasure Island (FL)2021.
2. Friedberg F, Winnick T, Greenberg DM. Peptide synthesis in vivo. J Biol Chem. 1947;169(3):763.
3. Ahmed ME, Dong Y, Lu Y, Tucker D, Wang R, Zhang Q. Beneficial Effects of a CaMKIIalpha Inhibitor TatCN21 Peptide in Global Cerebral Ischemia. J Mol Neurosci. 2017;61(1):42-51.
4. Steel R, Cowan J, Payerne E, O'Connell MA, Searcey M. Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction. ACS Med Chem Lett. 2012;3(5):407-410.
5. Kobayashi M, Yamamoto M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal. 2005;7(3-4):385-394.
6. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994;91(21):9926-9930.
7. Itoh K, Wakabayashi N, Katoh Y, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76-86.
8. Muttenthaler M, King GF, Adams DJ, Alewood PF. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021;20(4):309-325.
9. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655-672.
10. Katz AI, Emmanouel DS. Metabolism of polypeptide hormones by the normal kidney and in uremia. Nephron. 1978;22(1-3):69-80.