Setmelanotide monoacetate (RM-493 monoacetate) is a blood-brain barrier-permeable, selective MC4R agonist with a K i value of 2.1 nM for hMC4R. Setmelanotide monoacetate activates the CaMKK2/AMPK signaling pathway. Setmelanotide monoacetate mediates body weight homeostasis, feeding regulation and energy expenditure modulation; it reduces food intake, induces weight loss, decreases obesity severity, increases daytime activity and energy expenditure, lowers levels of leptin, triglycerides, fasting insulin and diastolic blood pressure, improves insulin sensitivity, glucose tolerance and fatty liver condition, and reverses respiratory depression. Setmelanotide monoacetate is applicable to research related to obesity, hyperinsulinemia, fatty liver and respiratory depression [1] [2] [3] [4] [5].
In Vivo, Setmelanotide monoacetate (300 nmol/kg/day; subcutaneous injection; continuous administration for 14 days) induces weight loss, improves hyperinsulinemia, reduces total cholesterol and leptin levels, and reverses hepatic steatosis in diet-induced obese C57BL/6J mice[1]. Monoacetate of Setmelanotide (6.4 μmol; intraperitoneal injection; single dose) acutely improves glucose clearance in leptin-deficient obese and glucose-intolerant C57BL/6J mice[1]. Monoacetate of Setmelanotide (6.4 μmol; intraperitoneal injection; single dose) suppresses refeeding-induced food intake in C57BL/6J mice fed a normal diet, and this effect depends on functional MC4R rather than MC3R[1]. Monoacetate of Setmelanotide (0.17-0.5 mg/kg/day; administered via a 2-week minipump every two weeks; for 8 weeks or variable duration) reduces peak body weight by 13.5% in diet-induced obese rhesus monkeys, improves insulin sensitivity and cardiovascular function, and does not cause adverse increases in heart rate or blood pressure; whereas lower doses only improve insulin sensitivity with minimal effects on body weight or cardiovascular parameters[2]. Monoacetate of Setmelanotide (0.05 mg/kg; i.p.; single administration) activates PVN MC4R neurons via the CaMKK2/AMPK signaling pathway, thereby normalizing food intake during short-term refeeding in rats with hypothalamic obesity[3]. Setmelanotide monoacetate (0.05 mg/kg; i.p.; once daily) activates PVN MC4R neurons via the CaMKK2/AMPK signaling pathway, reduces food intake, body weight, Lee index and perirenal adipose tissue weight, thereby reversing hypothalamic obesity in rats[3]. Monoacetate of Setmelanotide (6.4 µmole-1.34 mg/kg/day; intraperitoneal injection, subcutaneous injection; single injection, daily administration; for 14 consecutive days) induces MC4R-dependent feeding suppression and body weight loss in diet-induced obese mice[4]. Monoacetate of Setmelanotide (100-500 nmol/kg; subcutaneous injection; single administration) suppresses food intake in fasted male Sprague-Dawley rats[4]. Monoacetate of Setmelanotide (1 mg/kg; i.p.; single administration) effectively treats morphine-induced opioid-induced respiratory depression (OIRD) in lean male C57BL/6J mice by increasing respiratory rate and reducing apnea index, without impairing opioid analgesic effects[5]. Monoacetate of Setmelanotide (1 mg/kg; i.p.; single administration) effectively treats morphine-induced opioid-related respiratory depression in obese male C57BL/6J mice by increasing respiratory rate and reducing the frequency and duration of apnea, without affecting opioid analgesic effects[5].
In Vitro, Setmelanotide binds to hMC1R, MC3R, MC4R and rat MC4R with high affinity, while it shows weak binding affinity to hMC5R[1]. Setmelanotide monoacetate (increasing concentrations; treated at 37°C for 40 min) acts as an agonist to stimulate cAMP production in CHO-K1 cells expressing hMC1R, hMC3R, hMC4R, and rat MC4R; it shows weak activity on hMC5R and no activity on mouse MC2R[1]. Setmelanotide is a potent agonist of hMC4R, with a binding Ki of 2.1 nM and a cAMP EC50 of 0.27 nM in CHO-K1 cells, and exhibits low potency against hMC1R, hMC3R and hMC5R[4]. Setmelanotide (>1.0×10−6 M) has no affinity for the μ-opioid receptor, as its IC50 exceeds 1.0×10−6 M in competitive radioligand binding assays[5].
References:
[1]. Kumar KG, et al. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900.
[2]. Kievit P, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62(2):490-497.
[3]. Peng J, et al. Setmelanotide-mediated MC4R activation improves hypothalamic obesity via CaMKK2/AMPK pathways. Front Pharmacol. 2026;16:1730786. Published 2026 Jan 12.
[4]. Sharma S, et al. Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation. Molecules. 2019;24(10):1892. Published 2019 May 16.
[5]. Amorim MR, et al. Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression. bioRxiv [Preprint]. 2026 Mar 10:2026.03.08.708886. doi: 10.64898/2026.03.08.708886. PMID: 41959165; PMCID: PMC13061029.
In Vivo, Setmelanotide monoacetate (300 nmol/kg/day; subcutaneous injection; continuous administration for 14 days) induces weight loss, improves hyperinsulinemia, reduces total cholesterol and leptin levels, and reverses hepatic steatosis in diet-induced obese C57BL/6J mice[1]. Monoacetate of Setmelanotide (6.4 μmol; intraperitoneal injection; single dose) acutely improves glucose clearance in leptin-deficient obese and glucose-intolerant C57BL/6J mice[1]. Monoacetate of Setmelanotide (6.4 μmol; intraperitoneal injection; single dose) suppresses refeeding-induced food intake in C57BL/6J mice fed a normal diet, and this effect depends on functional MC4R rather than MC3R[1]. Monoacetate of Setmelanotide (0.17-0.5 mg/kg/day; administered via a 2-week minipump every two weeks; for 8 weeks or variable duration) reduces peak body weight by 13.5% in diet-induced obese rhesus monkeys, improves insulin sensitivity and cardiovascular function, and does not cause adverse increases in heart rate or blood pressure; whereas lower doses only improve insulin sensitivity with minimal effects on body weight or cardiovascular parameters[2]. Monoacetate of Setmelanotide (0.05 mg/kg; i.p.; single administration) activates PVN MC4R neurons via the CaMKK2/AMPK signaling pathway, thereby normalizing food intake during short-term refeeding in rats with hypothalamic obesity[3]. Setmelanotide monoacetate (0.05 mg/kg; i.p.; once daily) activates PVN MC4R neurons via the CaMKK2/AMPK signaling pathway, reduces food intake, body weight, Lee index and perirenal adipose tissue weight, thereby reversing hypothalamic obesity in rats[3]. Monoacetate of Setmelanotide (6.4 µmole-1.34 mg/kg/day; intraperitoneal injection, subcutaneous injection; single injection, daily administration; for 14 consecutive days) induces MC4R-dependent feeding suppression and body weight loss in diet-induced obese mice[4]. Monoacetate of Setmelanotide (100-500 nmol/kg; subcutaneous injection; single administration) suppresses food intake in fasted male Sprague-Dawley rats[4]. Monoacetate of Setmelanotide (1 mg/kg; i.p.; single administration) effectively treats morphine-induced opioid-induced respiratory depression (OIRD) in lean male C57BL/6J mice by increasing respiratory rate and reducing apnea index, without impairing opioid analgesic effects[5]. Monoacetate of Setmelanotide (1 mg/kg; i.p.; single administration) effectively treats morphine-induced opioid-related respiratory depression in obese male C57BL/6J mice by increasing respiratory rate and reducing the frequency and duration of apnea, without affecting opioid analgesic effects[5].
In Vitro, Setmelanotide binds to hMC1R, MC3R, MC4R and rat MC4R with high affinity, while it shows weak binding affinity to hMC5R[1]. Setmelanotide monoacetate (increasing concentrations; treated at 37°C for 40 min) acts as an agonist to stimulate cAMP production in CHO-K1 cells expressing hMC1R, hMC3R, hMC4R, and rat MC4R; it shows weak activity on hMC5R and no activity on mouse MC2R[1]. Setmelanotide is a potent agonist of hMC4R, with a binding Ki of 2.1 nM and a cAMP EC50 of 0.27 nM in CHO-K1 cells, and exhibits low potency against hMC1R, hMC3R and hMC5R[4]. Setmelanotide (>1.0×10−6 M) has no affinity for the μ-opioid receptor, as its IC50 exceeds 1.0×10−6 M in competitive radioligand binding assays[5].
References:
[1]. Kumar KG, et al. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900.
[2]. Kievit P, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62(2):490-497.
[3]. Peng J, et al. Setmelanotide-mediated MC4R activation improves hypothalamic obesity via CaMKK2/AMPK pathways. Front Pharmacol. 2026;16:1730786. Published 2026 Jan 12.
[4]. Sharma S, et al. Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation. Molecules. 2019;24(10):1892. Published 2019 May 16.
[5]. Amorim MR, et al. Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression. bioRxiv [Preprint]. 2026 Mar 10:2026.03.08.708886. doi: 10.64898/2026.03.08.708886. PMID: 41959165; PMCID: PMC13061029.