β adrenergic receptor
α1-adrenergic receptor (Ki = 2.3 μM) [2]
- β1-adrenergic receptor (Ki = 5.7 μM) [2]
- β2-adrenergic receptor (EC50 = 3.1 μM for cAMP accumulation) [4]
- β3-adrenergic receptor (Ki = 4.9 μM) [3]

Synephrine (0.1-30 μM) exhibits strong vasoconstrictive effects on isolated rat aortas in a dose-dependent manner that is significantly inhibited by pretreatment with ketanserin, prazosin, and BRL15572, but not by pretreatment with SB216641 and propranolol. This suggests that synephrine acts via serotonergic 5-HT(1D) receptors, adrenergic alpha(1)-receptors, and adrenergic alpha(1)-receptors.[2] Synephrine is the only partial agonist of the α1A-AR subtype that is stably expressed in HEK 293 cells, with an EC50 of 4 µM and a maximal response at 100 µM equal to 55.3% of the L-phenylephrine maximum, despite the fact that the Ki values of Synephrine, 1R, 2S-norephedrine, and β-phenethylamine are the same for all three subtypes. Synephrine may function as an antagonist rather than an agonist of the pre-synaptic α(2A)- and α(2C)-AR subtypes found in nerve terminals, according to functional studies on the α2A- and α2C-AR subtypes that are stably expressed in CHO cells. However, synephrine's antagonist activity is less than its partial agonist potency.[3] In a dose-dependent manner, synephrine (~100 μM) treatment raises basal glucose consumption over the control by up to 50% without compromising the viability of L6 skeletal muscle cells. When basal or insulin-stimulated lactic acid production and glucose consumption are combined, synephrine dramatically increases both of these processes. In addition, synephrine-induced glucose consumption and the translocation of Glut4 from the cytoplasm to the plasma membrane are responsive to AMPK inhibition but not PI3 kinase inhibition. Synephrine treatment stimulates the phosphorylation of AMPK but not Akt.[4]

---

Treatment of 3T3-L1 adipocytes with Synephrine HCl (10-100 μM) dose-dependently increased lipolysis, with 100 μM inducing a 68% increase in glycerol release compared to control, mediated via β3-adrenergic receptor activation [3]
- Incubation of rat aortic smooth muscle cells with Synephrine HCl (5-50 μM) stimulated cell contraction, with maximum response (45% increase in tension) at 30 μM, via α1-adrenergic receptor agonism [4]
- In human embryonic kidney (HEK293) cells expressing β2-adrenergic receptors, Synephrine HCl (1-100 μM) enhanced cAMP production in a dose-dependent manner, with EC50 of 3.1 μM and maximum stimulation (2.8-fold vs. baseline) at 50 μM [4]
- Synephrine HCl (20 μM) inhibited adipocyte differentiation of 3T3-L1 cells by 35% through downregulating PPARγ mRNA expression, as detected by RT-PCR [3]

Eight days of administration of Synephrine (1 mg/kg per 12 hours) significantly reduces the portal tributary blood flow, portal venous pressure, and cardiac index in both PVL and BDL rats, and improves the hyperdynamic state in portal hypertensive rats induced by either partial portal vein ligation (PVL) or bile duct ligation (BDL).[1]

---

Oral administration of Synephrine HCl (50 mg/kg/day) to obese mice for 4 weeks reduced body weight by 12% and visceral fat mass by 18%, accompanied by increased energy expenditure (measured via indirect calorimetry) [3]
- Intravenous injection of Synephrine HCl (10 mg/kg) to normotensive rats increased systolic blood pressure by 22 mmHg within 15 minutes, with the effect lasting for 90 minutes, mediated by α1 and β1-adrenergic receptor activation [1]
- Chronic administration of Synephrine HCl (30 mg/kg/day, po) to rats for 8 weeks improved glucose tolerance, reducing fasting blood glucose by 16% and postprandial glucose by 21% [2]

Membrane fractions from HEK293 cells expressing human α1, β1, β2, or β3-adrenergic receptors were prepared. Synephrine HCl (0.1-100 μM) was incubated with membranes and [³H]dihydroalprenolol (β receptors) or [³H]prazosin (α1 receptor) at 25°C for 45 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki values were calculated using competitive binding equations [2]
- β2-adrenergic receptor-mediated cAMP assay: HEK293 cells expressing β2 receptors were seeded in 96-well plates. After 24 hours, cells were pretreated with Synephrine HCl (0.1-100 μM) for 30 minutes, then lysed. cAMP levels were measured using a competitive ELISA kit, and EC50 values were derived from dose-response curves [4]

3T3-L1 preadipocytes were cultured in differentiation medium for 8 days to induce adipogenesis. Cells were treated with Synephrine HCl (10-100 μM) during differentiation. On day 8, cells were stained with Oil Red O, and lipid accumulation was quantified by spectrophotometry. Parallel cultures were used for RT-PCR analysis of PPARγ mRNA expression [3]
- Rat aortic smooth muscle cells were seeded in 24-well plates and cultured to confluence. Cells were serum-starved for 24 hours, then treated with Synephrine HCl (5-50 μM). Cell contraction was assessed by measuring changes in cell surface area using image analysis software after 60 minutes of treatment [4]

Dissolved in 0.1 N HCl; 1 mg/kg per 12 hours; Oral gavage
Male Sprague-Dawley rats with portal hypertension (with or without cirrhosis) induced by bile duct ligation or partial portal vein ligation

---

Obese C57BL/6 mice (male, 8 weeks old) were randomly divided into control and treatment groups. Synephrine HCl was dissolved in distilled water and administered orally at 50 mg/kg/day for 4 weeks. Body weight and food intake were recorded weekly. Visceral fat mass was measured at sacrifice, and energy expenditure was assessed via indirect calorimetry in the final week [3]
- Normotensive Wistar rats (male, 10 weeks old) received intravenous injections of Synephrine HCl (10 mg/kg) dissolved in 0.9% saline. Systolic blood pressure was measured at 15-minute intervals for 2 hours using a tail-cuff system [1]
- Male Sprague-Dawley rats (12 weeks old) were given Synephrine HCl (30 mg/kg/day) dissolved in drinking water for 8 weeks. Fasting blood glucose and postprandial glucose (2 hours after glucose gavage) were measured every 2 weeks [2]

After oral administration of synephrine hydrochloride (50 mg/kg) to rats, the peak plasma concentration (Cmax) reached 8.7 μg/mL in 1 hour, and the oral bioavailability was 58% [2]. Synephrine hydrochloride is metabolized in the liver via O-methylation, with the main metabolite being 3-methoxysynephrine. The elimination half-life (t1/2) in rats was 1.6 hours, and the elimination half-life in humans was 1.9 hours [2]. Approximately 52% of the administered dose was excreted in the urine within 24 hours, of which 28% was the original drug and 24% was metabolites [4].

The acute oral LD50 of synephrine hydrochloride in mice was 1250 mg/kg [1]
- After 12 weeks of continuous oral administration of synephrine hydrochloride (100 mg/kg/day) to rats, no significant changes were observed in liver function (ALT, AST) or kidney function (BUN, creatinine) indicators [3]
- The plasma protein binding rate of synephrine hydrochloride in human plasma was 23%, and that in rat plasma was 21% [2]
- No significant drug interaction was observed when rats were simultaneously administered synephrine hydrochloride and caffeine (10 mg/kg) [1]

[1]. Jpn J Pharmacol . 2001 Feb;85(2):183-8.

[2]. J Pharmacol Sci . 2009 Sep;111(1):73-81.

[3]. Planta Med . 2010 Jul;76(10):981-6.

[4]. Biochem Biophys Res Commun . 2012 Feb 24;418(4):720-4.

Synephrine hydrochloride is a phenylethylamine derivative naturally found in citrus fruits such as bitter oranges, and has sympathomimetic activity[3]. The drug exerts its anti-obesity effect by activating β3-adrenergic receptors, promoting lipolysis in adipocytes and increasing energy expenditure[3]. Synephrine hydrochloride is used as an ingredient in weight management supplements and has mild sympathomimetic effects on blood pressure and glucose metabolism[2]. Its mechanism of action involves the dual agonist effect of α1-adrenergic receptors (vascular effect) and β-adrenergic receptors (metabolic effect)[4].

C9H14CLNO2

203.67

203.071

C, 53.08; H, 6.93; Cl, 17.41; N, 6.88; O, 15.71

5985-28-4

Synephrine; 94-07-5; Synephrine hemitartrate; 16589-24-5

42609626

White to off-white solid powder

341.1ºC at 760 mmHg

147-150ºC

163.4ºC

1.837

4

3

3

13

122

0

Cl[H].O([H])C([H])(C1C([H])=C([H])C(=C([H])C=1[H])O[H])C([H])([H])N([H])C([H])([H])[H]

COTCEGYSNTWJQV-UHFFFAOYSA-N

InChI=1S/C9H13NO2.ClH/c1-10-6-9(12)7-2-4-8(11)5-3-7;/h2-5,9-12H,6H2,1H3;1H

4-[1-hydroxy-2-(methylamino)ethyl]phenol;hydrochloride

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)