<i>p</i>-Synephrine: A Novel Agonist for Neuromedin U2 Receptor

Abstract

In the brain, Neuromedin U2 receptor (NMU2R) is prominent in the hypothalamic regions and is known to be associated with regulation of several important physiological functions, including food intake, energy balance, stress response, and nociception. In this article, by random screening of compounds using the model of high-throughput screening for NMU2R stable expression, NMU2R negative and NMU2R short hairpin RNA (shRNA) knockdown HEK293 cell lines, for the first time, we discovered that p-synephrine, which is the primary protoalkaloid in Citrus aurantium (bitter orange) and is widely used in weight loss and weight management products, is a highly potent and selective NMU2R agonist. In NMU2R activating ability experiments, p-synephrine was found binding to NMU2R with high efficacy and potency; the efficacy, 50% of the maximum possible effect (EC 50 ) and potency values were determined to be 7.207, 6.604 and 0.227 µmol/L for the NMU2R, respectively. Our researches have important theoretical value for elucidating the mechanisms of p-synephrine in body weight and energy balance regulation. These data provide further evidence for widespread roles for p-synephrine and its receptors in the brain.

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine

“…p ‐Synephrine, the primary active constituent in bitter orange extracts, at least in part, exerts its effects through multiple mechanisms including its binding to β‐3 adrenergic receptors that regulate lipid and carbohydrate metabolism, NMUR2s, and AMP‐activated protein kinase, cAMP, and Ca(2+)‐dependent mechanisms (Hong et al ., ; Stohs et al ., ; Zheng et al ., ; de Oliveira et al ., ). Because p ‐synephrine exhibits little or no binding to α‐1, α‐2, β‐1, and β‐2 adrenergic receptors, p ‐synephrine exerts metabolic enhancement without acting as a central nervous system or cardiovascular stimulant at commonly used doses and therefore does not increase heart rate or blood pressure.…”

“…p-Synephrine binds up to 10 times more readily to adrenergic receptors in rodents than humans (Carpene' et al, 1999(Carpene' et al, , 2014Mercader et al, 2011), which can explain small cardiovascular effects in some animal studies at very high doses (Hansen et al, 2012(Hansen et al, , 2013. p-Synephrine, the primary active constituent in bitter orange extracts, at least in part, exerts its effects through multiple mechanisms including its binding to β-3 adrenergic receptors that regulate lipid and carbohydrate metabolism, NMUR2s, and AMP-activated protein kinase, cAMP, and Ca(2+)-dependent mechanisms (Hong et al, 2012;Zheng et al, 2014;de Oliveira et al, 2014). Because p-synephrine exhibits little or no binding to α-1, α-2, β-1, and β-2 adrenergic receptors, p-synephrine exerts metabolic enhancement without acting as a central nervous system or cardiovascular stimulant at commonly used doses and therefore does not increase heart rate or blood pressure.…”

“…Concentrations used in this study ranged from 0.001 to 1000 μM, with an effect detected at a concentration as low as 0.01 μM, a concentration within the range in serum produced by a single, typical 49‐mg oral dose of p ‐synephrine (Shara et al ., ). The concentration values that produced efficacy, 50% maximum possible effect (EC50), and potency were 7.2, 6.6, and 0.227 μM, respectfully (Zheng et al ., ). These results provide a possible and plausible mechanism for the reported appetite suppression and eating control that has been observed in both human and animal studies in conjunction with p ‐synephrine and bitter orange extract.…”

“…It has been shown that p-synephrine suppresses appetite and enhances eating control in humans (Kaats and Stohs, 2017) and animals (Arbo et al, 2009). Neuromedin U2 receptor (NMUR2) is present in the hypothalamic regions of the brain and is associated with regulation of food intake, energy balance, stress, and nociception (Zheng et al, 2014). In a study involving the use of NMUR2 negative and short hairpin RNA knockdown HEK293 cell lines, p-synephrine was shown to bind to this receptor with high efficacy and potency.…”

Effects of <em>p</em>-synephrine in combination with caffeine: a review

“…53 NMUR2 is present in the hypothalamic regions of the brain and is associated with regulation of food intake, energy balance, stress, and nociception.…”