title: Effects of synephrine and beta-phenethylamine on human alpha-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.
authors.affiliation: The National Center for Natural Products Research, The University of Mississippi, University, MS 38677, USA.
authors.forename: Guoyi
authors.initials: G
authors.lastname: Ma
authors.forename: Supriya A
authors.initials: SA
authors.lastname: Bavadekar
authors.forename: Brian T
authors.initials: BT
authors.lastname: Schaneberg
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Feller
mesh_terms: D000322:Adrenergic Agonists / Q000737:chemistry / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D020926:Medetomidine / Q000494:pharmacology; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D010665:Phenylpropanolamine / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013578:Synephrine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D010627:Phenethylamines; D010936:Plant Extracts; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D005576:Colforsin; C029261:phenethylamine; D010665:Phenylpropanolamine; D000242:Cyclic AMP; D020926:Medetomidine; D013578:Synephrine