Effects of Synephrine andβ-Phenethylamine on Humanα-Adrenoceptor Subtypes

Abstract

Synephrine and beta-phenethylamine, two naturally occurring compounds, are structurally related to ephedrine. In this study, the effects of synephrine and beta-phenethylamine on alpha-adrenergic receptor (alpha-AR) subtypes are investigated in human embryonic kidney (HEK293) or Chinese hamster ovary (CHO) cells, and compared to that of 1R,2S-norephedrine. The rank order of binding affinities was found to be the same for the subtypes tested (alpha(1A)-, alpha(2A)-, and alpha(2C)-AR) viz, 1R,2S-norephedrine > beta-phenethylamine > synephrine. Functional studies on the alpha(1A)-AR subtype showed that synephrine was a partial agonist giving a maximal response at 100 microM that was equal to 55.3 % of the L-phenylephrine maximum. In contrast, neither 1R,2S-norephedrine nor beta-phenethylamine exhibited agonist activity at the highest concentration tested (300 microM). beta-Phenethylamine was more potent as an antagonist than 1R,2S-norephedrine and synephrine on the alpha(1A)-AR subtype. Functional studies on the alpha(2A)- and alpha(2C)-AR subtypes indicated that synephrine and beta-phenethylamine did not act as agonists. Similar to 1R,2S-norephedrine, both of these analogs reversed the effect of medetomidine against forskolin-induced cAMP elevations at 300 microM, and the rank order of antagonist potency was: 1R,2S-norephedrine = beta-phenethylamine > synephrine; and beta-phenethylamine > 1R,2S-norephedrine > synephrine, respectively. These differences suggest that the presence of a 4-hydroxy group, as in synephrine, reduced the potency in these subtypes. In conclusion, at the alpha(1A)-AR, synephrine acted as a partial agonist, while beta-phenethylamine did not exhibit any direct agonist activity. Both, synephrine and beta-phenethylamine, may act as antagonists of pre-synaptic alpha(2A/2C)-ARs present in nerve terminals.

Modulation of Resistance Artery Tone by the Trace Amine β-Phenylethylamine: Dual Indirect Sympathomimetic and α1-Adrenoceptor Blocking Actions

“…We found that PEA is able to displace [ (Ma et al, 2010). Based on this result, we then used a functional assay to show that PEA could selectively reverse a 1 -adrenoceptor-mediated increases in vascular tone.…”

“…a 2 -adrenoceptors expressed in Chinese hamster ovary cells (K i ∼8 mM; Ma et al, 2010). The a 2 -adrenoceptor antagonist rauwolscine also increased nerve-mediated vasoconstriction in the perfused mesenteric bed and has previously been shown to act as a sympathomimetic agent by increasing noradrenaline outflow in the vasculature (Rump et al, 1992).…”

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

“…41) The cardiovascular effects of m-synephrine and p-synephrine were clearly distinct as a result of their markedly different adrenergic receptor binding activities, with m-synephrine exerting markedly greater binding to various α-receptor subtypes as well as β-1 and β-2 receptors. 9,[42][43][44] The well documented cardiovascular effects of m-synephrine cannot therefore be extrapolated to p-synephrine and bitter orange extract. So Stohs et al indicated that receptor binding studies involving tissues indicate that exhibits poor binding affinities or non-specificities for α-adrenoreceptor subtypes as well as β-1 and β-2 adrenoreceptors.…”

“…7,8) And p-synephrine was likely also to be binding to α-as well as β-1 and β-2 adrenoreceptors resulted in cardiovascular effects including increased cardiovascular contractility, heart rate and bronchodilation. 9,10) However, Stohs et al indicated that receptor binding studies involving tissues from humans and animals indicate that psynephrine exhibits poor binding affinities or non-specificities for α-adrenoreceptor subtypes as well as β-1 and β-2 adrenoreceptors. 11) Neuromedin U2 receptor (NMU2R), one of the two neuromedin U (NMU) receptors, was G protein-coupled receptors (GPCRs) formerly known as "orphan" receptor FM3/GPR66 and FM4.…”

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

“…m-Synephrine does not occur in nature, is not present in BOEs, 44 and is not permitted in dietary supplements. Ma et al 45 concluded that p-synephrine acts as an antagonist, rather than an agonist, with respect to human α 2A -and α 2C -adrenergic receptors. Jordan et al 46 concluded that p-synephrine bound to β 1 -and β 2 -adrenergic receptors about 10,000-fold less actively than norepinephrine.…”