Effects of synephrine and beta-phenethylamine on human alpha-adrenoceptor subtypes.

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.

Pseudolaric acid analogs as a new class of peroxisome proliferator-activated receptor agonists.

Extracts of the root and trunk barks of the Chinese tree Pseudolarix kaempferi, which contain pseudolaric acids, are used in Chinese medicine for treatment of fungal infections. Pseudolaric acid B (PLAB) is the major constituent that exhibits anti-fungal activity. The nuclear peroxisome proliferator-activator receptors (PPAR) were proposed as a cellular target for the action of PLAB and its analogs. PLAB and two derivatives were tested for the activation of PPAR isoforms in two mammalian cell lines. CV-1 and H4IIEC3 cells were transfected with phorbol ester response element or PPAR response element reporter constructs, and CV-1 cells were co-transfected with the individual PPAR isoform expression plasmids. PLAB showed similar concentration-dependent effects for the activation of PPAR alpha, gamma and delta isoforms in CV-1 and H4IIEC3 cells. O-Deacetylation of PLAB (PLAC) or esterification of the free carboxy group of PLAB with beta-D-O-glucopyranoside (PLAG) markedly reduced or abolished the activation of these PPAR isoforms. In H4IIEC3 cells, PLAB increased the activation of endogenous PPARalpha and the phospholipase C signaling pathway; and stimulated peroxisomal fatty acyl-CoA oxidase activity. These effects of PLAB on the activation of endogenous PPARalpha and phospholipase C-dependent pathway were blocked by staurosporine. These results suggest that the action of PLAB on PPARalpha in H4IIEC3 cells is mediated by a protein kinase C dependent phosphorylation. Based upon these findings, the chemical class of biologically active diterpene acids related to PLAB may have promise for the treatment of metabolic and pathophysiological disorders that are regulated by these nuclear receptor isoforms.