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 Author's personal copy

JOURNAL OF FUNCTIONAL FOODS 4 ( 2 0 1 2 ) 2 –5

Available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/jff

Stereochemical and pharmacological differences between

naturally occurring p-synephrine and synthetic p-synephrine

Sidney J. Stohsa,*, Harry G. Preussb

a
Creighton University Medical Center, Omaha, NE 67178, USA
b
Departments of Biochemistry, Medicine and Pathology, Georgetown University Medical Center, Washington, DC 22039, USA

A R T I C L E I N F O A B S T R A C T

Article history: p-Synephrine, the primary protoalkaloid in Citrus aurantium (bitter orange) and some other
Received 1 September 2011 Citrus species, exists in nature in the l- or [R-( )]-enantiomeric form, whereas synthetic p-
Received in revised form synephrine is a racemic mixture of the l- and d-enantiomeric forms. Based on receptor
21 September 2011 binding, the synthetic form is believed to exert approximately half the pharmacological
Accepted 22 September 2011 activity of the naturally occurring protoalkaloid. This difference occurs because the d- or
Available online 15 October 2011 [S-(+)]-form provides little or no binding to adrenergic receptors in contrast to the l-form.
Receptor binding studies also provide an explanation for the differences in pharmacologi-
Keywords: cal effects between the isomers p-synephrine and m-synephrine.
Citrus aurantium Ó 2011 Elsevier Ltd. All rights reserved.
Bitter orange
p-Synephrine
l- or [R]-Enantiomeric form
d- or [S]-Enantiomeric form
Racemic mixture

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1. Introduction tary supplements as well as sports performance products.

p-Synephrine is also widely consumed in various juices and
p-Synephrine is the primary protoalkaloid in Citrus aurantium food products as marmalades from Citrus species as Seville
(bitter orange) and some other Citrus species (Stohs, Preuss, & oranges, Marrs sweet oranges, grapefruit and mandarin as
Shara, 2011a). Bitter orange extract containing p-synephrine well as other orange-related species (Dragull, Breksa, & Cain,
is extensively used in weight loss/weight management die- 2008; Uckoo, Jayaprakasha, Nelson, & Patil, 2010). p-Syneph-

* Corresponding author: Address: 4967 Stillwater Trail, Frisco, TX 75034, USA. Tel.: +1 214 215 6655.
E-mail address: sstohs@yahoo.com (S.J. Stohs).
1756-4646/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jff.2011.09.004
 Author's personal copy
JOURNAL OF FUNCTIONAL FOODS
Fig. 1 – Enantiomeric structures of p-synephrine.
rine is a phenylethanolamine derivative with the hydroxyl
group in the para position on the benzene ring of the molecule
(Fig. 1).
In recent years, synthetic p-synephrine has been marketed
as an alternative to the naturally occurring Citrus-derived p-
synephrine. A question that arises is whether differences ex-
ist in the adrenoreceptor binding properties and accordingly
in the pharmacological effects of p-synephrine that is derived
from natural sources as fruits of C. aurantium and other Citrus
species versus p-synephrine that is chemically synthesized.
The answer to this question is yes, and the reason for the dif-
ferences is described below.
Confusion also exists in the literature (Bent, Padula, &
Neuhaus, 2004; Haaz, Williams, Fontaine, & Allison, 2010;
Penzak et al., 2001; Rossato, Costa, Limberger, de Lourdes Bas-
tos, & Remiao, 2010) concerning the pharmacological effects
of p-synephrine because there is also m-synephrine (phenyl-
ephrine) with the hydroxyl group located in the meta (number
2) position of the benzene ring as opposed to the para (number
1) position for p-synephrine (Fig. 1). m-Synephrine does not
occur naturally in Citrus species. Pellati and Benvenuti (2007)
reviewed 19 analytical studies of protoalkaloids in Citrus spe-
cies, and in no case was m-synephrine detected. Furthermore,
m-synephrine is not present in standardized bitter orange ref-
erence materials from the National Institute of Standards and
Technology (Evans, Pho, Roman, & Betz, 2008; Sander et al.,
2008). As will be discussed below, markedly different receptor
binding properties exist between the two synephrine isomers
resulting in markedly differing pharmacological effects.
2. Discussion
Synthetic p-synephrine is a mixture of the l- and d-enantio-
meric forms (Kusu, Matsumoto, Arai, & Takamura, 1996; Mer-
cader, Wanecq, Chen, & Carpene, 2011), which are also known
as the R-( )- and S-(+)-forms, respectively (Pellati, Cannazza,
& Benvenuti, 2010). The chemical structures and enantio-
meric configurations are presented in Fig. 1. The l-form of p-
synephrine is the form found in nature (fruits) while the d-
form does not occur in fruits as C. aurantium (Kusu et al.,
1996; Pellati, Benvenuti, Melegar, & Firenzuoli, 2002; Pellati,
Benvenuti, & Melegari, 2005; Pellati et al., 2010). However,
small amounts of the d-form of p-synephrine can be produced
in the extraction and isolation process depending on the pro-
cedures and conditions used (Kusu et al., 1996; Pellati et al.,
2010). For example, p-synephrine racemization is possible
4 ( 2 01 2 ) 2–5 3
when high temperatures are used in the isolation process at
both acidic and basic pH values (Pellati et al., 2010). Further-
more, when isolating conjugated p-synephrine from the urine
after ingestion of p-synephrine containing products, some of
the natural l-form may undergo chiral conversion to the d-
form during hydrolysis of the conjugate (Kusu et al., 1996).
The natural l-form of p-synephrine is synthesized from the
l-form of the amino acid tyrosine (Bartley, Breska, & Ishida,
2010). The l-forms of amino acids are predominantly present
in plants, and only l-forms of amino acids are incorporated
into proteins in mammalian systems and not the d-forms.
The synthesis of p-synephrine from l-tyrosine in plant sys-
tems such as C. aurantium readily provides an explanation
for the occurrence of the l-form of p-synephrine in plants as
opposed to the dl mixture or the d-form.
Numerous studies have shown that, in general, one enan-
tiomer of an enantiomeric pair reacts with receptors as an
agonist much more readily than the other enantiomer due
to the stereochemical differences, and numerous drugs are
now being developed based on these principles (Erb, 2006).
Furthermore, differences in pharmacokinetic properties oc-
cur as a result of the stereochemical differences between
enantiomeric pairs of molecules (Metz, Vakily, & Mulford,
2009).
Receptor binding studies have shown that the natural l-
form of p-synephrine much more readily binds to adrenore-
ceptors than the d-form. Jordan, Thonoor, and Williams
(1987) demonstrated in guinea pig atria and trachea that the
l-forms of p-synephrine and m-synpephrine bound to b1-
adrenoreceptors 40,000-fold and 100-fold, respectively, less
readily than nor-epinephrine. The d-forms of the two isomers
exhibited approximately 100-fold less binding to the b1-adre-
noreceptors than the corresponding l-forms. The l-forms of
p-synephrine and m-synephrine were about 10,000-fold less
active in binding to b2-adrenoreceptors than nor-epinephrine,
while the d-forms of the two isomers exhibited no detectable
binding activity.
Based on these results (Jordan et al., 1987), the d-enantio-
meric form of p-synephrine does not exert adrenergic activity.
Binding to b1- and b2-adrenoreceptors is associated with in-
creased heart rate and blood pressure (Inchiosa, 2011). How-
ever, the d-form of p-synephrine exhibited essentially no
binding to these b-adrenoreceptors, while the l-form of p-
synephrine exhibited very low binding affinity relative to
nor-epinephrine, indicating that it would exhibit very little
cardiovascular activity. The lipolytic activity of p-synephrine
 Author's personal copy
4 JOURNAL OF FUNCTIONAL FOODS
is believed to be due to binding to b-3 adrenoreceptors in tis-
sues (Stohs, Preuss, & Shara, 2011b).
Brown et al. (1988) examined the binding activities of the l-
and d-forms of p-synephrine and m-synephrine to a1-adreno-
receptors in rat aorta and a2-adrenoreceptors from rabbit
saphenous vein. The l-form of m-synephrine was 6-fold less
active than nor-epinephrine in binding to a1-adrenoreceptors
and 150-fold less active in binding to a2-adrenoreceptors. The
l-form of p-synephrine was 1000-fold less active in binding to
both a-adrenoreceptors than nor-epinephrine. In addition,
the d-form of p-synephrine exhibited over 100-fold lower
binding activity than the l-form of p-synephrine, indicating
that the d-form would not be expected to exert adrenergic
activity. These results affirm the observations of Jordan
et al. (1987) with respect to the lack of receptor binding for
the d-form of p-synephrine and provide a mechanistic expla-
nation for the cardiovascular effects of m-synephrine and the
lack of cardiovascular effects for p-synephrine.
Ma, Bavadeka, Schaneberg, Khan, and Feller (2010) have
shown that p-synephrine is approximately 50-fold less potent
than m-synephrine in activating human a1a-adrenoreceptors,
and has even lower binding affinity for human a2a- and a2c-
adrenoreceptor subtypes. Furthermore, they concluded that
p-synephrine may act as an antagonist of pre-synaptic a2a-
and a2c-adrenoreceptors. All of these a-receptor subtypes
are involved in local and systemic vasoconstriction, and stim-
ulation results in increased blood pressure (Inchiosa, 2011).
Hwa and Perez (1996) examined the structural features
necessary for binding to and activation of the a1a-adrenore-
ceptor. They concluded that it is the meta-hydroxy of
endogenous agonists as m-synephrine (phenylephrine) that
hydrogen bonds to a serine moiety at the receptor site, and
not the para-hydroxy that results in receptor activation. Thus,
m-synephrine will bind to and activate the receptor resulting
in vasoconstriction and an increase in blood pressure, while
p-synephrine would have little or no effect. As a consequence,
p-synephrine would be expected to have little effect on blood
pressure relative to m-synephrine or nor-epinephrine (Stohs
et al., 2011a, 2011b).
Based on these observations, it can be concluded that the
synthetic dl-mixture of p-synephrine will be much less active
than the natural l-form of p-synephrine for preparations
containing the same per cent of synthetic versus natural
p-synephrine. Only approximately half of the synthetic
p-synephrine mixture will be active and bind to receptors
based on the receptor binding studies (Brown et al., 1988; Jor-
dan et al., 1987; Ma et al., 2010). The enantiomeric d-form of
p-synephrine may have no effect on the binding of the active
l-form, may decrease the activity of the active l-form by inter-
fering with its binding to the receptor, may act as a weak
antagonist, or may exert an exceedingly weak agonistic activ-
ity (Brown et al., 1988; Jordan et al., 1987; Ma et al., 2010; Stohs
et al., 2011b). Furthermore, the resulting effect may be con-
centration dependent.
The above described effects for the enantiomers of
p-synephrine are consistent with receptor binding studies
for a variety of drugs. Over one-third of the prescription drug
market involves single enantiomeric drug products (Erb,
2006). It is well known that a dl mixture of a drug will have
less activity than of one of the two enantiomers because
4 ( 2 0 1 2 ) 2 –5
one of the two enantiomers will exhibit little or no receptor
binding activity due to the stereochemical differences. Single
enantiomer drugs are becoming increasingly common due to
advances in synthesis and separation techniques (Wang, Ouy-
ang, & Baeyens, 2008). The switch from the racemic proton
pump inhibitor drug omeprazole to the single enantiomeric
form esomeprazole (Nexiumâ) is an excellent example of this
growing market (Lind et al., 2000).
Other similar examples exist among common biologically
active molecules. dl-a-Tocopherol is the chemically synthe-
sized form of vitamin E. However, d-a-tocopherol is the form
that exists in nature, and is the form that has been shown to
exert beneficial physiological effects (Brigelius-Flohe et al.,
2002; Hacquebard & Carpentier, 2005). The synthetic dl-race-
mic mixture exhibits approximately half the physiological po-
tency of the natural d-form (Blatt, Pryor, Mata, & Rodrigue-
Proteau, 2004). Furthermore, the use of the dl-mixture when
conducting studies on the mechanisms of action of vitamin
E as well on determining the physiological roles of vitamin
E has resulted in much confusion and conflicting results for
obvious reasons (Blatt et al., 2004).
Another example of the importance of the stereochemis-
try of a molecule is a-lipoic acid which is an important biolog-
ical antioxidant and is widely used in dietary supplements as
the dl [R-(+)/S-( )] racemic mixture. However, it is the natu-
rally occurring R-(+)-enantiomer that is essential in mito-
chondrial dehydrogenase reactions and protects membranes
by interacting with vitamin C and glutathione (Moini, Packer,
& Saris, 2002; Packer, Witt, & Tritscher, 1995).
3. Summary
The naturally occurring l-form of p-synephrine as is present
in Citrus juices, food products and extracts will exhibit
approximately twice the physiological activity as compared
to an equal weight of the synthetic dl-enantiomeric mixture
of p-synephrine. Direct comparative studies have not been
conducted to date to confirm observations based on adreno-
receptor binding.
Conflict of interest
The authors have received no funding or remuneration for
this article. The authors have served as consultants for Nutra-
tech Inc.
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