RO27-3225 is a selective melanocortin-4 receptor (MC4R) agonist with EC₅₀ values of 0.6 nM at MC4R, 4.8 nM at MC3R, and >10,000 nM at MC1R and MC5R. [1]
Functions as a potent and selective MC4R agonist. [2][3]

RO27-3225 is a cyclic heptapeptide (Ac-Cys¹⁰-[D-Nal⁷,Arg⁸]-Cys⁹-NH₂) with 1,000-fold selectivity for MC4R over MC1R/MC5R. [1]
Mechanism: Activates MC4R to modulate central appetite regulation and peripheral anti-inflammatory pathways. [1][2]
Confers neuroprotection by promoting angiogenesis and suppressing neuroinflammation post-stroke. [3]

In freely feeding rats, intraperitoneal injection of RO27-3225 (0.01-1 mg/kg) dose-dependently reduced food intake by up to 90% at 1 mg/kg within 4 hours without inducing conditioned taste aversion. This effect was absent in MC4R knockout mice. [1]
In a rat hemorrhagic shock model, intravenous administration of RO27-3225 (90 μg/kg) restored mean arterial pressure (MAP) from 30±5 mmHg to 85±10 mmHg within 15 minutes, improved organ perfusion, and reduced plasma TNF-α and IL-6 levels by >50%. [2]
In mice with middle cerebral artery occlusion (MCAO), daily intraperitoneal injection of RO27-3225 (0.5 mg/kg for 14 days) increased neurogenesis (BrdU⁺/DCX⁺ cells by 2.5-fold), enhanced PDGFRβ⁺ pericytes recruitment, and reduced microglial activation (Iba1⁺ cells decreased by 40%). [3]

Food intake study: Rats/mice received RO27-3225 (0.01, 0.1, 1 mg/kg) or vehicle via intraperitoneal (i.p.) injection. Food consumption was measured 1-4h post-dosing. Taste aversion assessed by sucrose preference after drug pairing. [1]
Hemorrhagic shock model: Rats subjected to 45% blood loss received RO27-3225 (90 μg/kg) or vehicle intravenously at 60 min post-shock. Hemodynamics monitored for 6h; organs harvested for histology/cytokine analysis. [2]
Stroke recovery model: MCAO mice treated with RO27-3225 (0.5 mg/kg i.p. daily for 14 days) starting 24h post-surgery. Brains analyzed by immunohistochemistry and ELISA at day 15. [3]

RO27-3225 (1 mg/kg intraperitoneal injection) did not induce conditioned taste aversion, nor did it impair motor coordination in the rotarod test. [1]
In rats with hemorrhagic shock, no acute toxicity was observed at 90 μg/kg intravenous injection. [2]
In MCAO mice, no behavioral abnormalities or deaths were reported after 14 days of intraperitoneal treatment at 0.5 mg/kg. [3]

[1]. A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences. J Neurosci. 2000 May 1;20(9):3442-8.

[2]. Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage. Br J Pharmacol. 2007 Mar;150(5):595-603.

[3]. Effects of RO27-3225 on neurogenesis, PDGFRβ+ cells and neuroinflammation after cerebral infarction. Int Immunopharmacol. 2020 Feb 11;81:106281.

Studies using non-selective agonists and antagonists of melanocortin-3 receptor (MC3R) and MC4R have demonstrated the important role of the melanocortin system in controlling food intake in the central nervous system. This paper describes a novel compound exhibiting highly selective agonist activity towards the MC4 receptor, while showing minimal activity towards the MC3 receptor. Central injection of this selective agonist into rats increased Fos-like immunoreactivity in the paraventricular nucleus, central amygdala, nucleus of the solitary tract, and posterior pole, a neuronal activation pattern similar to that induced by non-selective MC3/4R agonists. Furthermore, central injection of this compound into rats or peripheral injection into db/db mice lacking functional leptin receptors suppressed food intake through a mechanism without disease or other non-specific effects. Conversely, a related selective MC4R antagonist significantly increased food intake in rats upon central administration. These results support the hypothesis that brain MC4R is closely associated with food intake and weight control, and provide evidence that selective activation of MC4R leading to anorexia is not secondary to an aversion effect. [1]

---

Background and Objectives: Melanocortin plays a life-saving role in circulatory shock, which may be mediated by the MC4 receptor. To directly understand the role of the melanocortin MC4 receptor in hemorrhagic shock, we investigated the effects of two novel selective MC4 receptor agonists. Methods: A severe hemorrhagic shock model was established in rats under general anesthesia. Rats were then treated with the non-selective agonist [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP-MSH) or the selective MC4 agonists RO27-3225 and PG-931, respectively. Cardiovascular and respiratory function were continuously monitored for 2 hours; survival rate was recorded within 24 hours. Free radicals in the blood were measured by electron spin resonance spectroscopy; tissue damage was histologically assessed at 25 minutes or 24 hours after treatment. Main Results: All rats receiving saline treatment died within 30–35 minutes. NDP-MSH, RO27-3225 and PG-931 treatments all dose-dependently (13-108 nmol kg-1 intravenous injection) restored cardiovascular and respiratory function and improved survival. These three melanocortin agonists also significantly reduced circulating free radical levels compared with saline-treated shock rats. All of these effects could be prevented by pretreatment with the selective MC4 receptor antagonist HS024 via intraperitoneal injection. In addition, RO27-3225 treatment prevented morphological and immunocytochemical changes in the heart, lungs, liver and kidneys in the early (25 min) and late (24 h) stages. Conclusion and significance: Stimulation of MC4 receptors can reverse hemorrhagic shock, reduce multi-organ damage and improve survival. Our results suggest that selective MC4 receptor agonists may have a protective effect against multi-organ failure following circulatory shock. [2] Cerebral infarction imposes a severe social and economic burden on patients due to its high incidence and mortality, and existing treatments are limited. RO27-3225 is a highly selective melanocortin receptor 4 agonist that can alleviate damage caused by various neurological diseases, such as cerebral hemorrhage, traumatic brain injury, and chronic neurodegenerative diseases. However, the effect of RO27-3225 on cerebral infarction remains unclear. This study used a mouse model of transient middle cerebral artery occlusion (tMCAO) and administered RO27-3225 or saline via intraperitoneal injection. Results showed that on day 7 after tMCAO, RO27-3225 increased the number of Nestin+/BrdU+ cells and dicortin (DCX)+/BrdU+ cells in the subventricular zone (SVZ), as well as the number of DCX+/BrdU+ cells in the peri-infarct region. In addition, on day 3 after tMCAO, RO27-3225 reduced the number of activated microglia (Iba1+ cells with a specific morphology) in the peri-infarct area and decreased the expression levels of Iba1, TNFα, IL6 and iNOS proteins, while increasing the number of PDGFRβ+ cells. Finally, mice treated with RO27-3225 showed a significant reduction in infarct volume, brain water content and neurological deficits after cerebral infarction. Therefore, RO27-3225 can improve the prognosis after cerebral infarction, partly through regulating neurogenesis in the SVZ, survival of PDGFRβ+ cells and neuroinflammation in the peri-infarct area. Our study suggests that RO27-3225 is a potential new therapy for cerebral infarction. [3]

C39H52N12O6

784.906987190247

898.406

1373926-49-8

274682-89-2;1057258-86-2 (free base isomer);1373926-49-8 (TFA);1051970-60-5 (3 TFA);

146026285

{Butir}-His-{dPhe}-Arg-Trp-{Sar}-NH2{Butir}-H-{dPhe}-RW-{Sar}-NH2

{Butir}-H-{dPhe}-RW-{Sar}-NH2

Off-white to light yellow solid

10

13

22

64

1470

4

CCCC(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N(C)CC(=O)N.C(=O)(C(F)(F)F)O

XBNXUPIBUGBMCO-WYDLTDSDSA-N

InChI=1S/C39H52N12O6.C2HF3O2/c1-3-10-34(53)47-31(19-26-21-43-23-46-26)37(56)49-30(17-24-11-5-4-6-12-24)36(55)48-29(15-9-16-44-39(41)42)35(54)50-32(38(57)51(2)22-33(40)52)18-25-20-45-28-14-8-7-13-27(25)28;3-2(4,5)1(6)7/h4-8,11-14,20-21,23,29-32,45H,3,9-10,15-19,22H2,1-2H3,(H2,40,52)(H,43,46)(H,47,53)(H,48,55)(H,49,56)(H,50,54)(H4,41,42,44);(H,6,7)/t29-,30-,31-,32-;/m0./s1

(2S)-N-[(2S)-1-[(2-amino-2-oxoethyl)-methylamino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-[[(2S)-2-(butanoylamino)-3-(1H-imidazol-5-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-5-(diaminomethylideneamino)pentanamide;2,2,2-trifluoroacetic acid

RO27-3225; 1373926-49-8; RO273225; RO27-3225; (2S)-N-[(2S)-1-[(2-amino-2-oxoethyl)-methylamino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-[[(2S)-2-(butanoylamino)-3-(1H-imidazol-5-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-5-(diaminomethylideneamino)pentanamide;2,2,2-trifluoroacetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (with ultrasonication)
H2O: ~100 mg/mL (with ultrasonication)

Solubility in Formulation 1: ≥ 2.5 mg/mL (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

Solubility in Formulation 3: ≥ 2.5 mg/mL (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well.

---

View More

Solubility in Formulation 4: 100 mg/mL in PBS (add these co-solvents sequentially from left to right, and one by one), Clear solution.

---

 (Please use freshly prepared in vivo formulations for optimal results.)