Obesity is a chronic disease manifested by an excess of fat mass in proportion to body size. Today, every third American is considered overweight (Body Mass Index (BMI) >25 kg/m2), thus prompting the United States Centers for Disease Control and Prevention (CDC) to declare that obesity is reaching epidemic proportions (Cummings and Schwartz, Annu. Rev. Med. 54:453-471 ((2003)). The importance of treating obesity is emphasized by the fact that this disease is either the underlying cause, or a risk factor, for developing diseases such as Type 2 Diabetes, congestive heart failure, osteoarthritis and sleep apnea among others.
Additionally, obesity is linked to “Metabolic Syndrome” which is a medical condition characterized by obesity, atherogenic dyslipidemia, elevated blood pressure and insulin resistance. Metabolic Syndrome affects an increasing number of people in the United States. Importantly, it has been shown that even a modest decrease in body weight (5-10% of initial body weight) may significantly improve Metabolic Syndrome conditions and decrease the risk factors for developing obesity-associated disease (Wing et al., Arch. Intern. Med. 147:1749-1753 (1987); Tuomilehto et al., New Engl. J. Med. 344:1343-1350 (2001); Knowler et al., New Engl. J Med. 346:393-403 (2002); Franz et al., Diabetes Care 25:148-198 (2002)). Additionally, treatment of obesity may be important from a mental health perspective due to the social stigma often attached to obese individuals in some cultures.
Melanocortin receptors play a major role in the regulation of overall energy balance and obesity in both humans and rodents. Alpha-melanocyte stimulating hormone (alpha-MSH) is a 13 amino acid peptide hormone that is an important component of the melanocortin system. Alpha-MSH is produced by the proteolytic processing of proopiomelanocortin (POMC) released by the pituitary gland. Alpha-MSH binds with high affinity to the melanocortin 4 receptor (MC4R), but also binds melanocortin receptor 3 (MC3R) and melanocortin receptor 5 (MC5R) with lower affinity. MC4R is a G-coupled protein receptor found in the brain which, when stimulated by alpha-MSH binding, causes decreased food intake and increased fat oxidation. Ultimately, stimulation of melanocortin receptors such as MC4R results in weight loss.
In humans and rodents, loss of function mutations in the different components of the melanocortin system are closely correlated with obesity and related conditions. In mice, mutations within POMC, or MC4R and MC3R produce obesity, insulin resistance and hyperphagia (Goodfellow and Saunders, Curr. Topics Med. Chem. 3: 855-883 (2003); Huszar et al., Cell 88:131-141 (1997); Yaswen et al., Nat. Med. 5: 1066-1070 (1999)). In man, mutations within POMC or MC4R lead to the development of obesity associated with increased food intake (Krude et al., Nat. Genet. 19:155-157 (1998); Yeo et al., Nature Genetics 20:111-112 (1998); Branson et al., New Engl. J. Med. 348: 1096-1103 (2003); Vaisse et al., J. Clin. Invest. 106):253-262 (2000); Ho and MacKenzie, J. Biol. Chem. 275: 35816-35822 (1999)).
Weight loss can result from the pharmacological stimulation of melanocortin system activity. In rodents pharmacological stimulation of melanocortin receptors such as MC4R leads to decreased food intake, increased energy expenditure and weight loss (Pierroz et al., Diabetes 51: 1337-1345 (2002)). In man, the intranasal administration of alpha-MSH to stimulate MC4R in non-obese men results in decreased body weight due to the loss of fat—but not lean body mass (Fehm et al., J. Clin. Endo. Metabol. 86: 1144-1148 (2001)).
Obesity is currently treated, with only limited success, by several different strategies. These strategies primarily involve “life-style” changes (e.g., diet and exercise), small molecule-based pharmaceutical therapies or surgical removal of a portion of the stomach (gastric by-pass surgery). Additionally, weight loss stimulating melanocortin receptor binding peptides such as alpha-MSH are of limited use as pharmaceuticals due to the extremely short serum half-life of such peptides.
Alpha-MSH also plays a role in enhancing male erectile activity. Targeting the melanocortin receptor with the synthetic melanocortin receptor activator molecule melanotan II (MTII) produced an unexpected side effect of enhancing erectile dysfunction (20). MTII has also been shown to initiate erections in rodents and humans without sexual stimulation in contrast to selective MC4 receptor agonists. Thus, both MC3 and MC4 receptors are likely necessary for complete proerectile erections. Clinical data showed a statistically significant erectile response in healthy male subjects following intranasal or subcutaneous administration of the MTII derivative, PT-141 (bremelanotide) (22, 23). Male erectile dysfunction (ED) is currently treated primarily with PDE5 inhibitors such as VIAGRA®, CIALIS® and LEVITRA®. However, these agents are required to be taken orally approximately one hour before sexual activity.
Bremelanotide is also being tested for use in treating female sexual dysfunction (FSD). The American Foundation for Urologic Disease defines FSD as: “The persistent or recurrent inability to attain or maintain sufficient sexual excitement, causing personal distress. It may be expressed as a lack of subjective excitement or a lack of genital or other somatic responses.” FSD consists of four components, hypoactive sexual desire disorder, female sexual arousal disorder (FSAD), anorgasmia and dyspareunia. Some form of FSD appears to be prevalent in approximately 43 percent of the female population. Laumann et al., JAMA 281, 537-544 (1999).
Alpha-MSH also functions as a cytokine antagonist that inhibits inflammation caused by some of the most prominent mediators of local inflammation (31). For example, alpha-MSH inhibits production and action of proinflammatory cytokines and chemokines (32, 33). Alpha-MSH also inhibits macrophage production of cytotoxic nitric oxide (NO) and neopterin (34,35), prostaglandin E synthesis (37). Alpha-MSH also activates descending anti-inflammatory neural pathways dependent on peripheral beta 2-adrenergic receptors (38) and increases production of interleukin-10 (39).
In allergic inflammation, the anti-inflammatory effects of alpha-MSH peptides were confirmed in acute skin inflammation induced by nonspecific irritants and cytokines (42-46). In addition to its suppressive effect on induction and elicitation of contact hypersensitivity, alpha-MSH induces hapten-specific tolerance in mice through IL-10 release (47).
In gouty (acute) arthritis, ACTH had an anti-inflammatory effect in a rat model of gouty arthritis. The same authors also showed that targeting MC3R subtype could be useful for clinical management of human gouty arthritis and possibly other acute arthritis (48). In rheumatoid arthritis, treatment of rats, who had a preclinical adjuvant-induced rheumatoid arthritis, with alpha-MSH significantly reduced joint pathology. Effectiveness of alpha-MSH was reported to be similar to that of prednisolone.
In inflammatory bowel disease, alpha-MSH administered to mice with dextran sulfate-induced colitis had reduced fecal blood and less weight loss compared to mice receiving placebo (51). Alpha-MSH administration reduced colonic macroscopic lesions in both acute and chronic colitis induced by trinitrobenzosulfonic acid in rats (52).
In a mouse model of bilateral renal ischemia, alpha-MSH significantly reduced ischemia-induced renal damage (32).
In liver inflammation and fibrosis, alpha-MSH gene therapy reversed established liver fibrosis in CCl4-treated mice (60). In another study, alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration and increased hepatic mRNA abundance for TNF-alpha and neutrophil and monocyte chemokines (33).
In ischemic brain damage (stroke), alpha-MSH treatment abolishes intracerebral proinflammatory cytokine gene expression after transient cerebral ischemia and indicates that systemically administered melanocortins may exert neuroprotective effects in cerebral ischemia. This study showed that alpha-MSH reduced activation of intracerebral TNF-alpha and IL1 beta gene expression after arterial occlusion and reperfusion (40). In another study, melanocortins provided strong protection, with a broad therapeutic window, against inflammatory, apoptotic (incl DNA damage), and histopathological and behavioral consequences of brain ischemia by activating CNS melanocortin 4 (MC4) receptors (41).
In peripheral neuropathies, alpha-MSH and ACTH demonstrated that both peptides stimulated axonal outgrowth from fetal spinal cord slices in vitro in a dose-dependent manner (53). Also, alpha-MSH promoted sprouting and neurite elongation from dissociated rat spinal and sensory neurons (55).
A need exists for additional treatments for the conditions discussed above and in particular for melanocortin receptor binding molecules with a potentially fast onset of action that overcome the short serum half-life of melanocortin receptor binding peptides such as alpha-MSH.
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