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.

Ephedra species of plants have both beneficial and adverse effects primarily associated with the presence of ephedrine alkaloids. Few reports have appeared that examine the direct actions of ephedrine alkaloids on human subtypes of adrenergic receptors (ARs). In the present study, ephedrine alkaloids were evaluated for their binding affinities on human ␣ 1A -, ␣ 1B -, ␣ 1D -, ␣ 2A -, ␣ 2B -, and ␣ 2C -AR subtypes expressed in HEK and Chinese hamster ovary cells. Cell-based reporter gene assays were used to establish functional activity of ephedrine alkaloids at ␣ 1A -, ␣ 2A -, and ␣ 2C -ARs. The data showed that ephedrine alkaloids did not activate ␣ 1 -and ␣ 2 -ARs and that they antagonized the agonist-mediated effects of phenylephrine and medetomidine on ␣ 1 -and ␣ 2 -ARs, respectively. As in the binding studies, 1R,2R-and 1R,2S-ephedrine showed greater functional antagonist activity than the 1S,2R-and 1S,2S-isomers. The rank order of affinity for the isomers was 1R,2R Ͼ 1R,2S Ͼ 1S,2R Ͼ 1S,2S. The rank order of potencies of alkaloids containing a 1R,2S-configuration was norephedrine Ն ephedrine Ͼ Ͼ N-methylephedrine. These studies have demonstrated that orientation of the ␤-hydroxyl group on the ethylamino side chain and the state of N-methyl substitution are important for ␣-AR binding and functional activity of the ephedrine alkaloids. In conclusion, the ephedrine isomers and analogs studied did not exhibit any direct agonist activity and were found to possess moderate antagonist activities on cloned human ␣-ARs.

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In a hen, large quantities of the egg yolk proteins apolipoprotein (apo) II and vitellogenin (VG), are expressed in the liver and transported to the oviduct during egg production. Estrogenic stimulation of the hepatic expression of apo II and VG is due to both transcriptional increase and mRNA stabilization. The nucleolytic degradation of apo II mRNA is prevented by estrogen-regulated mRNA stabilizing factor (E-RmRNASF). Gene-specific effects of a select panel of SERMs on the hepatic expression of the estrogen-responsive genes encoding apo II, VG and E-RmRNASF in the chicken liver were investigated. In the present study, 6-week-old roosters were treated with the vehicle, estrogen, the SERMs genistein, resveratrol, tamoxifen, pterostilbene, raloxifene, catechin and clomiphene or a combination of estrogen and a 200-fold excess of each of the SERMs. Results from mRNA stabilization studies, conducted to investigate the stimulation of expression of E-RmRNASF in the liver by these agents showed that the expression of E-RmRNASF in the liver, was stimulated by estrogen, and the SERMs genistein, resveratrol, tamoxifen, pterostilbene, and catechin, but not by the vehicle, clomiphene or raloxifene. The expression of apo II and VG from the above treatments was determined by Northern blot analysis, RNase protection assays and Western blot analysis. The transcription and protein expression of both apo II and VG genes were seen in response to treatment with estrogen but not with the SERMs or combinations of estrogen and each of the SERMs. The SERMs that stimulated the expression of E-RmRNASF, antagonized the stimulation of the expression of both apo II and VG by estrogen, demonstrating a gene-specific, selective regulation of the above genes in the chicken liver by the SERMs. The above panel of SERMs may likely have adverse effects on egg production.

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