Effects of Synephrine and β-Phenethylamine on Human α-Adrenoceptor Subtypes

Abstract

Synephrine and β-phenethylamine, two naturally occurring compounds, are structurally related to ephedrine. In this study, the effects of synephrine and β-phenethylamine on α-adrenergic receptor (α-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 (α _1A-, α _2A-, and α _2C-AR) viz, 1R,2S-norephedrine > β-phenethylamine > synephrine. Functional studies on the α _1A-AR subtype showed that synephrine was a partial agonist giving a maximal response at 100 µM that was equal to 55.3 % of the L-phenylephrine maximum. In contrast, neither 1R,2S-norephedrine nor β-phenethylamine exhibited agonist activity at the highest concentration tested (300 µM). β-Phenethylamine was more potent as an antagonist than 1R,2S-norephedrine and synephrine on the α _1A-AR subtype. Functional studies on the α _2A- and α _2C-AR subtypes indicated that synephrine and β-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 µM, and the rank order of antagonist potency was: 1R,2S-norephedrine = β-phenethylamine > synephrine; and β-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 α _1A-AR, synephrine acted as a partial agonist, while β-phenethylamine did not exhibit any direct agonist activity. Both, synephrine and β-phenethylamine, may act as antagonists of pre-synaptic α _2A/2C-ARs present in nerve terminals.

Key words

synephrine - β‐phenethylamine - α‐adrenoceptors - partial agonist - radioligand binding assay - cyclic‐AMP

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