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(The FASEB Journal. 2005;19:497-502.)
© 2005 FASEB

N-Coumaroyldopamine and N-caffeoyldopamine increase cAMP via beta 2-adrenoceptors in myelocytic U937 cells

Jae B. Park1

Phytonutrients Laboratory, BHNRC, ARS, USDA, Beltsville, Maryland, USA

1Correspondence: Jae B. Park, Ph.D., Phytonutrients Laboratory, Bldg. 307C, Rm. 131, BHNRC, ARS, USDA, Beltsville, MD 20705, USA. E-mail: parkj{at}ars.usda.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
N-Caffeoyldopamine is a phytochemical found in various plants, including cocoa (Theobroma cacao L.). N-caffeoyldopamine and its natural analogs (N-cinnamoyldopamine, N-coumaroyldopamine, N-feruloyldopamine, and N-sinapoyldopamine) were synthesized and investigated to determine their potency as ß-adrenoceptor agonists, because they have chemical structural moieties found in ß-adrenoceptor agonists. Among the compounds tested in this study, N-coumaroyldopamine and N-caffeoyldopamine were the two most potent compounds, able to increase cAMP at the concentrations < 0.05 µM in U937 cells. The decreasing order of potency was N-coumaroyldopamine > N-caffeoyldopamine > N-feruloyldopamine > N-sinapoyldopamine > N-cinnamoyldopamine. Using ß2-specific antagonists (butoxamine and ICI 118551), N-coumaroyldopamine and N-caffeoyldopamine were found to increase cAMP via ß2-adrenoceptors in U937 cells. In producing cAMP in U937 cells, N-coumaroyldopamine and N-caffeoyldopamine were as potent as several well-known ß2-adrenoceptor agonists (salbutamol, procaterol, and fenoterol). These results indicate that N-coumaroyldopamine and N-caffeoyldopamine are potent compounds able to increase cAMP via ß2-adrenoceptors in U937 cells, and may have potential effects on human health.—Park, J. B. N-Coumaroyldopamine and N-caffeoyldopamine increase cAMP via beta 2-adrenoceptors in myelocytic U937 cells.


Key Words: phytochemical • cardiac disease • ß-adrenoceptor agonist • cocoa


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ADRENOCEPTORS are involved in various biological functions related to human health such as cardiovascular, pulmonary, and metabolic functions (1 2 3 4) . Adrenoceptors consist of {alpha}- and ß-type adrenoceptors with several subtypes (5 6 7 8 9) . ß-Adrenoceptors play important physiological roles in cardiac stimulation, bronchodilation, thermogenesis, and others (10 11 12 13) . Due to these physiological characteristics, ß-adrenoceptor agonists have been developed and used clinically to treat symptoms originating from cardiac and pulmonary diseases (14 15 16) . Plants are believed to contain potent compounds affecting ß-adrenoceptors and are commonly used to alleviate symptoms from heart diseases and pulmonary dysfunctions often treated with ß-adrenoceptors agonists (17 18 19 20) .

In my laboratory, phytochemicals belonging to a group of phenylpropenic acid amides have been synthesized and their potential health effects have been investigated in human cells. N-Caffeoyldopamine is a phytochemical that belongs to this group and is found in various plants, including cocoa (Theobroma cacao L.). N-Caffeoyldopamine has chemical structural moieties found in ß-adrenoceptor agonists such as dobutamine and denopamine (21 22 23 24 25 26) . Therefore, N-caffeoyldopamine and its analogs (N-cinnamoyldopamine, N-coumaroyldopamine, N-feruloyldopamine, and N-sinapoyldopamine) were synthesized and investigated to determine their potency as ß-adrenoceptor agonists.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials
Salbutamol, procaterol, fenoterol, dobutamine, butoxamine, caffeic acid, ferulic acid, sinapic acid, dopamine, and other chemicals were purchased from Sigma Chemical Co. (St. Louis, MO, USA). U937 cells were purchased from ATCC (Manassas, VA, USA).

Cell culture conditions
U937 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. Cell viability was determined microscopically by Trypan blue exclusion and the number of cells was counted by hematocytometer (27) .

Syntheses and confirmation of N-caffeoyldopamine and its analogs
Syntheses were performed as described previously (28 , 29) . Briefly, the appropriate phenylpropenic acids (cinnamic acid, coumaric acid, caffeic acid, ferulic acid, and sinapic acid) were dissolved in dichloromethane and converted to the symmetrical anhydride with 1,3-diisopropylcarbodiimide. Dopamine was added to the reaction mixture, then stirred gently for 1 h. The synthesized products were recovered as described (28) . Synthesized N-caffeoyldopamine and its analogs were purified by HPLC (Waters, Milford, MA, USA). For analysis by LC-MS, samples were purified further as described (28) . LC-MS was performed with an Agilent HP-1100 liquid chromatograph equipped with a Phenomenex LUNA C18 column (150x4.26 mm, 5 µ), operated at 25°C at a flow rate of 0.2 mL/min using the elution buffer containing 0.1% formic acid as described (28) .

Measurement of cAMP
The measurements of cAMP were performed using Assay Designs’ Correlate-EIATM Direct cyclic AMP kit based on a competitive immunoassay. Briefly, 2 x 106 U937 cells were treated with ß-adrenoceptor agonists N-caffeoyldopamine or its analogs for 10 min, washed three times with cold PBS buffer, and centrifuged. According to the manufacturer’s protocol, the pallet was lysed and the lysate was incubated in the well coated with the antibody binding cAMP. Excess reagents were washed away and p-nitrophenyl phosphate was added. After 5 min incubation, the reaction was stopped and the yellow color generated was read on a microplate reader at 405 nm. The intensity of the bound yellow color is inversely proportional to concentrations of cAMP in the samples. The optical density measured is used to calculate the concentration of cAMP. The compounds (N-caffeoyldopamine and its analogs) used in the assays were > 98% pure.

Kinetic analyses
Data points in all figures represent the mean of three or more samples ±SD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Syntheses and LC-MS/MS/MS analyses of N-cinnamoyldopamine, N-coumaroyldopamine, N-caffeoyldopamine, N-feruloyldopamine, N-sinapoyldopamine
N-Cinnamoyldopamine, N-coumaroyldopamine, N-caffeoyldopamine, N-feruloyldopamine, and N-sinapoyldopamine were synthesized using dopamine and phenylpropenic acids (cinnamic acid, coumaric acid, caffeic acid, ferulic acid, and sinapic acid), respectively. Their chemical structures differ in the positions and number of hydroxyl groups on the benzene ring (Fig. 1 ). The syntheses were simple, and the yield of each analog was > 40%. Synthesized products were purified by HPLC and analyzed by LC-MS as described in Materials and Methods. The major signals from the peaks in LC-MS were obtained at estimated mass/charge (m/z) units of 283.3, 300.1, 315.1, 329.1, and 359.1, which are identical to the (m/z) units of N-cinnamoyldopamine, N-coumaroyldopamine, N-caffeoyldopamine, N-feruloyldopamine, and N-sinapoyldopamine (data not shown). Because all LC-MS procedures produced similar analyses of the five analogs, only the LC-MS and MS/MS data of N-coumaroyldopamine are presented here. As shown in Fig. 2 , the synthesized N-coumaroyldopamine produced two signals: a minor (251.1 m/z) and a major (300.1 m/z). The minor signal seemed to be attributed to a contaminant, because the signal was almost undetectable after further purification of the synthesized compound (data not shown here). Meanwhile, the major signal obtained at estimated mass/charge (m/z) units of 300 is likely to result from the synthesized N-coumaroyldopamine. To unambiguously identify the major signal as N-coumaroyldopamine, MS/MS experiments were performed using the product of the major signal in LC-MS. MS/MS chromatogram showed one peak (147 m/z) derived from daughter ion spectrums after the loss of elements C8H11NO2, which is consistent with the dopamine portion of the molecule (data not shown). The data indicated clearly that the compound in the peak of the LC-MS was N-coumaroyldopamine.



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  		Figure 1. Chemical structures of N-caffeoyldopamine and its analogs. Chemical structures for cinnamic acid, coumaric acid, caffeic acid, ferulic acid, sinapic acid, dopamine, N-cinnamoyldopamine (I), N-coumaroyldopamine (II), N-caffeoyldopamine (III), N-feruloyldopamine (IV), and N-sinapoyldopamine (V).



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  		Figure 2. LC-MS chromatogram. Mass spectrum of the N-coumaroyldopamine detected at m/z (300). The mass spectrum is the full scan (m/z 100–500) with the background ions subtracted.

Effects of N-caffeoyldopamine and its analogs on increasing intracellular cAMP in U937 cells
Because N-cinnamoyldopamine, N-coumaroyldopamine, N-caffeoyldopamine, N-feruloyldopamine, and N-sinapoyldopamine have chemical structural moieties found in ß-adrenergic drugs such as dobutamine and denopamine (Fig. 1) , they were investigated to determine their ability to increase cAMP in the cells. In this study, myelocytic U937 cells were used to measure intracellular concentrations of cAMP because the cells possess ß-adrenoceptors with a high density of the ß2 subtype (30) . As shown in Fig. 3 , among the compounds tested, N-coumaroyldopamine was the most potent compound, able to increase cAMP > 8-fold that of basal cAMP concentrations in U937 cells. The decreasing order of the potency was N-coumaroyldopamine > N-caffeoyldopamine > N-feruloyldopamine > N-sinapoyldopamine > N-cinnamoyldopamine. The data indicate that 4 position hydroxylation in phenylpropenic acid moiety are critical in increasing cAMP, because the deletion of 4 position hydroxylation in the moiety (N-cinnamoyldopamine) significantly decreased its potency in producing cAMP. N-Caffeoyldopamine found in cocoa plant was almost as potent as N-coumaroyldopamine, which is able to increase cAMP at the concentrations < 0.05 µM in U937 cells. These data indicate that the 3 position hydroxylation in phenylpropenic acid moiety may not be critical in increasing cAMP in U937 cells because N-caffeoyldopamine was no more potent than N-coumaroyldopamine in producing cAMP in the cells. However, O-methylation of the 3 position hydroxyl group (N-feruloyldopamine) reduced the ability to increase cAMP noticeably, suggesting that O-methylation of hydroxyl groups in phenylpropenic acid moieties of N-caffeoyldopamine and N-coumaroyldopamine may attenuate their potency for increasing cAMP in the cells.



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  		Figure 3. The determination of the potency of N-caffeoyldopamine and its analogs in U937 cells. 2 x 106 U937 cells were treated for 10 min with each compound (N-cinnamoyldopamine, N-coumaroyldopamine, N-caffeoyldopamine, N-feruloyldopamine, or N-sinapoyldopamine) and cAMP was determined as described in Materials and Methods. Data points represent the mean ±SD of 3 or more samples.

The determination of N-coumaroyldopamine and N-caffeoyldopamine as ß-adrenoceptor agonists
Because N-coumaroyldopamine and N-caffeoyldopamine are potent compounds able to increase intracellular cAMP at the concentrations < 0.05 µM and because U937 cells possess a high level of ß-adrenoceptors, N-coumaroyldopamine and N-caffeoyldopamine were investigated to determine whether they are ß-adrenoceptor agonists that produce cAMP via ß-adrenoceptors in U937 cells. For blocking ß-adrenoceptors in U937 cells, three nonselective ß-adrenoceptor antagonists (alprenolol, pindolol, and propranolol) were pretreated before adding N-coumaroyldopamine or N-caffeoyldopamine. As shown in Fig. 4 A, B, N-coumaroyldopamine and N-caffeoyldopamine were unable to increase intracellular cAMP in the U937 cells pretreated with alprenolol, pindolol, or propranolol. The data indicate clearly that N-coumaroyldopamine and N-caffeoyldopamine increase intracellular cAMP via ß-adrenoceptors in U937 cells. To determine their potency as ß-adrenoceptor agonists, N-coumaroyldopamine, and N-caffeoyldopamine were compared with well-known ß-adrenoceptor agonists: isoproterenol (nonselective adrenoceptor agonist), dobutamine and arterenol (ß1-adrenoceptor agonist), and salbutamol (ß2-adrenoceptor agonist). The decreasing order of the potency was isoproterenol ≥ N-coumaroyldopamine ≥ salbutamol ≥ N-caffeoyldopamine > arterenol > dobutamine (data not shown here).



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  		Figure 4. Determination of N-coumaroyldopamine and N-caffeoyldopamine as ß-adrenoceptor agonists. 2 x 106 U937 cells were pretreated for 5 min with 3 nonselective ß-adrenoceptor antagonists (alprenolol, pindolol, and propranolol) before incubation with N-coumaroyldopamine (A) or N-caffeoyldopamine (B). Control was not pretreated with antagonists. Data points represent the mean ±SD of 3 or more samples.

N-Coumaroyldopamine and N-caffeoyldopamine produce cAMP via ß2-adrenoceptor in U937 cells
U937 cells contain ß-adrenoceptors with a high density of the ß2 subtype. Therefore, N-coumaroyldopamine and N-caffeoyldopamine are likely to produce cAMP via ß2-adrenoceptors in the cells (30 31 32) . To determine whether N-coumaroyldopamine and N-caffeoyldopamine produce cAMP via ß2-adrenoceptors in U937 cells, ß2-specific antagonists (butoxamine and ICI 118551) were used to block ß2-adrenoceptors. As shown in Fig. 5 A, N-coumaroyldopamine and N-caffeoyldopamine were not able to increase intracellular cAMP in U937 cells pretreated with butoxamine or ICI 118551. This indicates that N-coumaroyldopamine and N-caffeoyldopamine produce cAMP mainly via ß2-adrenoceptors in U937 cells. Since N-coumaroyldopamine and N-caffeoyldopamine were potent compounds able to produce cAMP mainly via ß2-adrenoceptors in U937 cells, they were compared with well-known ß2-adrenoceptor agonists (salbutamol, procaterol, and fenoterol). As shown in Fig. 5B , N-coumaroyldopamine and N-caffeoyldopamine were as potent as the ß2-adrenoceptor agonists in producing cAMP in U937 cells. The potency also reflects apparent Kd values for N-coumaroyldopamine, N-caffeoyldopamine, and salbutamol (0.69, 0.75, and 0.65 µM, respectively) obtained from Km values often used as an apparent dissociation constant (Fig. 5B ). Because N-coumaroyldopamine and N-caffeoyldopamine show strong ß2-adrenoceptor agonist activity, compounds and plants containing them are anticipated for use in preventing and/or treating various human diseases treated with ß-adrenoceptor agonists.



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  		Figure 5. Production of cAMP by N-coumaroyldopamine and N-caffeoyldopamine via ß2-adrenoceptors. A) 2 x 106 U937 cells were pretreated for 5 min with ß2-specific antagonists (butoxamine or ICI118551) before incubation with N-coumaroyldopamine or N-caffeoyldopamine. Control was not pretreated with the antagonists. B) N-coumaroyldopamine and N-caffeoyldopamine were compared with ß2-adrenoceptor agonists (salbutamol, procaterol, and fenoterol). Apparent Kd values for N-coumaroyldopamine, N-caffeoyldopamine, and salbutamol were obtained by determining Km values using Lineweaver-Burk reciprocal plot. Data points represent the mean ±SD of 3 or more samples.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
For last 5 years, phytochemicals belonging to a group of clovamide-type phenylpropenic acid amides (N-caffeoyldopamine and its analogs) have been investigated in my laboratory in order to determine their effects on ß-adrenoreceptors in human cells, because some phytochemicals belonging to the group have chemical structures strikingly similar to ß-adrenoceptor agonists used to treat pulmonary obstruction disease and cardiovascular diseases (5 6 7 8 9 10 11 12 13 14 15 16) . In plants, N-caffeoyldopamine is synthesized via conjugating caffeic acid and dopamine in an amide bond (21 22 23) . Because caffeic acid and dopamine can be substituted by other phenylpropenic acids (cinnamic acid, coumaric acid, ferulic acid, and sinapic acid) and tyrosine-derived bioamines, respectively, N-cinnamoyldopamine, N-caffeoyldopamine, N-feruloyldopamine, N-sinapoyldopamine, and their analogs are likely to be found in the plant (24 25 26) . In fact, several phenylpropenic acid amides such as N-caffeoyldopamine, clovamide (N-coumaroyltyrosine), deoxyclovamide, and N-caffeoyltyrosine have been identified from cocoa plant, and more new phenylpropenic acid amides are yet to be discovered from the plant (25) . There is a report that the phytochemical composition in cocoa plant may be influenced by genetic and environmental factors (25) . Therefore, it is possible that novel phytochemicals with potential health effects may be produced and their content may be modulated by genetic and environmental factors in the plant.

In this study, N-caffeoyldopamine and its analogs (N-cinnamoyldopamine, N-coumaroyldopamine, N-feruloydopamine, and N-sinapoyldopamine) were investigated to determine their potency as ß-adrenoceptor agonists in human myelocytic U937 cells. The data indicate that N-coumaroyldopamine and N-caffeoyldopamine are potent ß-adrenoceptor agonists. However, there is a slight possibility that the adrenoceptor agonist activity may be from precursors of N-coumaroyldopamine and N-caffeoyldopamine (coumaric acid, caffeic acid or dopamine). This possibility was eliminated because the precursors were not detected by HPLC in the assay mixtures and because they could not increase cAMP via ß2-adrenoceptors at the concentrations tested in this study (data not shown here).

Lately, health effects of cocoa powder on coronary heart disease have been suggested, but the basis for this protective mechanism remains undefined (33 34 35 36 37 38) . Coronary heart disease is a leading cause for human mortality in the U.S. Coronary artery disease results from atherosclerosis of the coronary arteries, which restricts blood flow to the heart. Atherosclerosis can be attributed to various pathophysiological conditions such as chronic inflammation, hypercholesterolemia, and platelet aggregation. Platelet aggregation is induced by several factors, but the aggregation can be inhibited by cAMP. Potential effects of ß-adrenoceptor agonists on platelet aggregation have been documented in vivo and in vitro models (39 40 41) . Numerous phytochemicals were reported to inhibit platelet aggregation, and their inhibitory mechanisms are under investigation (42 , 43) . Therefore, N-caffeoyldopamine and its analogs are currently under investigation in my laboratory to determine their potency to inhibit platelet aggregation via increasing cAMP in platelets. Preliminary data indicate that N-coumaroyldopamine and N-caffeoyldopamine inhibit > 60% expression of CD62P (a platelet activation marker) on platelet membranes induced by agonists such as collagen and thrombin. Ongoing and future studies will provide critical information regarding whether N-caffeoyldopamine and its analogs are able to inhibit platelet aggregation via increasing cAMP or other mechanisms.

In summary, N-coumaroyldopamine and N-caffeoyldopamine were synthesized and determined as potent compounds that produce cAMP via ß2-adrenoceptors in U937 cells. Beta-adrenoceptor agonists are therapeutic compounds developed solicitously and used clinically to treat various human diseases. Therefore, isolation, identification, and evaluation of novel phytochemicals as potential ß-adrenoceptor agonists will be subjected to future studies.

Received for publication July 26, 2004. Accepted for publication December 2, 2004.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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