J Pharmacol Sci 116, 137 – 148 (2011) Journal of Pharmacological Sciences

© The Japanese Pharmacological Society

Critical Review

Neuropsychotoxic and Neuroprotective Potentials of Dextromethorphan

and Its Analogs
Eun-Joo Shin1, Jae-Hyung Bach1, Sung Youl Lee1, Jeong Min Kim2, Jinhwa Lee2, Jau-Shyong Hong3,
Toshitaka Nabeshima4, and Hyoung-Chun Kim1,*
1
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University,
Chunchon 200-701, Korea
2
Central Research Center, Green Cross Corp, Yongin 446-799, Korea
3
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry,
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
4
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan

Received March 7, 2011; Accepted March 28, 2011

Abstract. Dextromethorphan (3-methoxy-17-methylmorphinan) has complex pharmacologic

effects on the central nervous system. Although some of these effects are neuropsychotoxic, this
review focuses on the neuroprotective effects of dextromethorphan and its analogs. Some of these
analogs, particularly dimemorfan (3-methyl-17-methylmorphinan) and 3-hydroxymorphinan, have
promising neuroprotective properties with negligible neuropsychotoxic effects. Their neuroprotec-
tive effects, the mechanisms underlying these effects, and their therapeutic potential for the treat-
ment of diverse neurodegenerative disorders are discussed.

Keywords: dextromethorphan, dimemorfan, 3-hydroxymorphinan, neuroprotection,

neuropsychotoxicity, neurodegenerative disorder

1. Introduction receptors and a neuroprotective agent. However, its

Dextromethorphan (DM, 3-methoxy-17-methylmor-
phinan), a common ingredient in more than 125 com-
mercial cough and cold remedies, is a dextrorotatory
optical isomer of levomethorphan, a typical morphine-
like opioid that is the codeine analog of the morphinan
derivative levorphanol. Patented by Hoffmann–La Roche
in 1954 as an antitussive agent, DM has strong safety and
efficacy profiles with no sedative or addictive properties
at recommended antitussive doses (1). As an antitussive,
DM is superior to opioids used at antitussive doses in that
it lacks their gastrointestinal side effects, such as consti-
pation, and causes less depression of the central nervous
system.
In the past decade, investigators have documented that
DM is an antagonist of N-methyl D-aspartate (NMDA)
neuroprotective effect is only seen at a dosage much
higher that that used for cough suppression. The psycho-
tropic effects that can result from the clinical use of high
doses of DM (2, 3) and the fact that DM has been recog-
nized as the object of drug-seeking behavior in several
countries (4, 5) have hampered its pharmacologic devel-
opment as a useful neuroprotective agent. In this review,
we will discuss the complex behavioral effects of DM;
demonstrate its neuroprotective effects; and discuss its
analogs, such as dimemorfan (DF, 3-methyl-17-methyl-
morphinan) and 3-hydroxymorphinan (3-HM), which
have neuroprotective effects with improved safety pro-
files. The chemical structures of DM and its analogs are
shown in Fig. 1.
2. Metabolism of DM

DM is rapidly absorbed from the gastrointestinal tract

*Corresponding author. kimhc@kangwon.ac.kr
into the bloodstream. At oral therapeutic doses, it begins
Published online in J-STAGE on May 21, 2011 (in advance)
doi: 10.1254/jphs.11R02CR to act within 15 – 30 min of administration, reaching its
peak serum level within 2 – 2.5 h (6, 7). It crosses the
Invited article blood–brain barrier with a cerebral spinal fluid/plasma

137

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This is an open access article under the CC BY-NC-ND License (http://creativecommons.org/licenses/by-nc-nd/ ).
138 E-J Shin et al

Codeine Dextromethorphan Dextrorphan

(DM) (DX)

3-Methoxymorphinan 3-Allyloxy- 3-Cyclopropylmethoxy-

(3-MM) 17-methylmorphinan 17-methylmorphinan
(3-AM) (3-CM)

Dimemorfan 3-Hydroxymorphinan
(DF) (3-HM) GCC1290K

Fig. 1. Chemical structures of codeine, dextromethorphan (DM), and DM analogs.

ratio of 33% – 80% (6) and a duration of action of 5 – 6
h (7).
DM is metabolized primarily through O-demethylation,
which produces dextrorphan (DX), and also to some ex-
tent through N-demethylation, which yields 3-methoxy-
morphinan. Both metabolites are further demethylated to
3-hydroxymorphinan (3-HM) (Fig. 2). Urinary recovery
studies in humans and rats have shown that that DX and
3-HM are excreted largely (> 95%) as glucuronide con-
jugates (8). The pharmacology of 3-methoxymorphinan
is not significant, and it does not have major behavioral
side effects. However, as discussed later in this review,
we have observed that 3-HM offers anti-parkinsonian
effects with absolute safety.
DX, the major metabolite of DM, has neuroprotective
potential (9). Its affinity for the NMDA Ca2+-channel
complex is lower than that of DM, but its affinity for the
phencyclidine [PCP, 1-(1-phenylcyclohexyl)piperidine]
binding site on the complex is higher than that of DM;
DX binding to the NMDA-receptor complex produces
PCP-like discriminative stimulus effects (10). The extent
of the metabolic conversion of DM to DX is highly de-
pendent on the route of administration (8); intraperitoneal
(i.p.) administration of DM, whereby it is absorbed into
the hepatic portal circulation, greatly favors production
of DX, while subcutaneous (s.c.) administration is less
favorable for DX production (8).
3. DM-induced neuropsychotoxicity
3.1. Behavioral side effects
Results of animal studies have suggested that most
symptoms observed in abusers of DM are caused by DX,
which binds to the same central nervous system receptors
 Neuromodulations by DM and Its Analogs
DM
CYP3A4 CYP2D6
3-MM DX
3-HM
Conjugated
CYP2D6 CYP3A4
DX
Conjugated
3-HM
Fig. 2. Metabolic pathway of DM. CYP=cytochrome P450, DM=
dextromethorphan, 3-MM=3-methoxymorphinan, DX=dextrorphan,
3-HM=3-hydroxymorphinan.
as PCP. In mice, long-term oral administration of a
neuroprotective dose of DM produces behavioral sup-
pression followed by behavioral tolerance, and prenatal
exposure to DM produces hyperlocomotor activity in the
offspring. When these offspring receive additional DM,
they demonstrate marked behavioral depression (11).
Mice exposed to long-term oral DM treatment exhibit
impaired B-cell function and natural killer-cell cytotoxic-
ity, similar to the immunosuppressive effects of PCP
(12).
Ample evidence indicates that DM has effects of its
own that are independent of its conversion to DX.
Holtzman (13) has reported that DM (30 mg/kg, s.c.) has
PCP-like discriminative effects that are independent of
its conversion to DX; these effects are most easily ap-
preciated in vitro, where metabolism is not an important
issue. Interestingly, DM (13) and DX (10) are completely
interchangeable for PCP in rats trained to distinguish
PCP from saline, and DM also substitutes for DX in pi-
geons trained to discriminate DX from saline (14).
Therefore, the route of administration is an important
determinant in the deposition of DM and its metabolites,
as well as in its behavioral effects.
DM alters the behavioral response to several drugs of
abuse, including morphine, methamphetamine, and co-
caine. DM (25 mg/kg, i.p.) reduces methamphetamine
139
self-administration in rats but does not affect the response
to a food reward (15). In addition, the co-administration
of DM (20 mg/kg, i.p.) with methamphetamine (2 mg/kg,
i.p.) attenuates methamphetamine-induced psychological
dependence [conditioned place preference (CPP)] and
behavioral sensitization (16). Pretreatment with DM (20
mg/kg, s.c.) potentiates the effects of acute morphine
exposure, while it attenuates the effects of chronic mor-
phine exposure on dopamine release in the nucleus ac-
cumbens (15).
Pulvierenti et al. (17) demonstrated that DM (25 mg/
kg, i.p.) reduces the self-administration of cocaine at
various doses (0.12, 0.25, and 0.5 mg/kg per 2-h infu-
sion) in rats, consistent with other findings (18). How-
ever, Kim et al. (18) reported that oral DM (40 mg/kg)
increases the rate of reinforced responses to lower doses
of cocaine (0.06 and 0.03 mg/kg per infusion). Therefore,
DM shifts the dose–response curve for cocaine self-ad-
ministration to the left, suggesting a sensitized response
to the reinforcing effects of cocaine. Consistent with this
interpretation, Jhoo et al. (19) reported that DM (i.p.) has
a biphasic effect on cocaine-induced psychological de-
pendence, as evaluated by CPP. DM decreases CPP in-
duced by high doses of cocaine and increases CPP in-
duced by low doses (19). Furthermore, Kim et al. (20)
found that DM exerts biphasic effects on cocaine-induced
locomotor stimulation in mice and that the locomotor
activities parallel Fos-related antigen immunoreactivity
in the striatal complex. Therefore, the cocaine-induced
behavioral response is influenced by pre-exposure to
DM, although the responses might also be affected by the
route, period, or interval of administration or by the ani-
mal model.
3.2. Neurotoxicity
A single exposure to a non-competitive NMDA-
receptor antagonist, such as MK-801, PCP, or ketamine,
has been reported to cause pathological damage in the
posterior cingulate cortex and retrosplenial cortex of rat
brain (21). These chemicals can induce heat shock pro-
tein HSP-70, which may play a role in cellular repair
and/or protective mechanisms in the same regions (22).
Hashimoto et al. (23) found that the induction of HSP-70
protein in the posterior cingulate and retrosplenial cortex
of the rat brain was maximal at a DM dose of 75 mg/kg
(i.p.). In contrast, Carliss et al. (24) found that high-dose
oral DM did not produce the neuropathologic changes
caused by other NMDA-receptor antagonists, suggesting
that the disposition of DM and its metabolites in rat brain
depends on the route of administration. However, our
preliminary findings (data not shown) indicate that an
understanding of the precise neuropathologic mecha-
nisms mediated by high-dose DM will require more
140 E-J Shin et al
study.
3.3. Cognitive dysfunction
Substantial evidence indicates that NMDA receptors
play a significant role in the synaptic plasticity (25) be-
lieved to form the basis for certain commonly studied
learning and memory processes involving the hippocam-
pus. Some forms of long-term potentiation, a putative
physiological process underlying learning and memory,
have been shown to be NMDA receptor–dependent (26).
Furthermore, many studies indicate that NMDA-receptor
antagonists that interfere with long-term potentiation
also disrupt performance on learning tasks, particularly
those involving spatial memory (27). Because NMDA
receptors are involved in both synaptic plasticity and
neurodegenerative processes, potential anticonvulsant/
neuroprotective drugs targeting this receptor must be
evaluated in terms of their possible interference with
normal learning and memory processes.
DM has been suggested to prevent the induction of
long-term potentiation in vivo (28). In addition, investi-
gators have demonstrated that DM (29) and DX (30)
impair passive avoidance in rats. Similarly, DM has been
reported to impair spatial learning in the Morris water
maze in a dose-dependent manner (31), consistent with
the water-maze effects of other NMDA-receptor antago-
nists (e.g., MK-801 and AP-5) reported by other investi-
gators (26). On the other hand, the memory impairment
caused by DX is more pronounced than that of DM (32),
and the prolonged use of DM produces cognitive deterio-
ration in humans (33).
4. Neuroprotective effects of DM
4.1. Anticonvulsant effects
DM has been reported to suppress seizures induced
by maximal electroshock (34, 35), NMDA (36, 37),
amygdala kindling (38, 39), kainic acid (40, 41),
BAY k-8644 (42, 43), and trimethyltin (44). DX (the
dextrorotatory form of levorphanol) has similarly been
reported to suppress seizures induced by maximal elec-
troshock (34), NMDA (36), and BAY k-8644 (42, 43).
Most studies have found that DX is several times more
potent than DM as an anticonvulsant, suggesting that the
metabolite formed in vivo significantly contributes to the
anticonvulsant activity of the parent drug (45). However,
some data suggest that the conversion of DM to DX is
not necessarily required for DM to produce its effects in
vivo (46). Both DM and DX show high binding affinities
for σ1-type receptors, but DM binds 2 – 5 times more
tightly than DX (47), despite the greater anticonvulsant
potency of DX. Thus, the mechanisms underlying the
anticonvulsant action of DM and DX remain unclear at
this point.
In addition to interacting with σ receptors, DM also
weakly inhibits NMDA receptor–mediated responses
(48, 49), which seems to be mediated by binding to a
non-competitive antagonist site of the NMDA-receptor
cation channel (50). Compared with DM, DX is several
times more potent as an NMDA-receptor antagonist (51),
which is consistent with its higher anticonvulsant effects
in vivo.
Noting that DM decreases seizure intensity in fully
kindled rats, Feeser et al. (38) have endorsed clinical
testing of DM as an anticonvulsant drug, but Takazawa
et al. (39) have demonstrated that DM has a narrow thera-
peutic window as an anticonvulsant for kindled seizures.
Furthermore, the active metabolite DX has been reported
to be ineffective against amygdala-kindled seizures (52).
Takazawa et al. (39) have also reported that treatment of
animals with DM (30 – 50 mg/kg body weight) leads to
hindlimb ataxia and sedation in a dose-dependent man-
ner, although without resting electroencephalographic
changes. The proconvulsant activity of DM may depend
on the experimental model, as Echevarria et al. (53) have
shown in rats that DM has anticonvulsant effects in the
maximal electroshock test and proconvulsant effects in
the flurothyl test.
Leander (37) has argued that antitussives have an an-
ticonvulsant action separate from their PCP-like blockade
of NMDA receptors. In this respect, a previous report
that DM and DX, but not MK-801, can effectively block
voltage-gated inward calcium and sodium currents in
neurons (54) is of considerable interest, as these effects
could explain why antitussives, but not more selective
NMDA-receptor antagonists such as MK-801, act as
anticonvulsants in kindling models. Indeed, it has been
suggested that the primary mechanism of action of DM
is simply a blockade of certain ion channels (9). In addi-
tion to its direct effects on voltage-gated cation channels,
DM might also have anticonvulsant effects resulting
from its binding to σ receptors (9, 34, 44, 47, 55),
although the role of σ receptors in anticonvulsant drug
actions remains to be determined. Both anticonvulsant
and proconvulsant effects have been reported for σ-site
ligands (9).
Radiolabeled DM binds to high-affinity sites in the
brain; these sites are strikingly similar in their binding
characteristics and regional distribution to σ-binding sites
and are modulated by the antiepileptic drug phenytoin (9,
45). Indeed, at least one of the high-affinity DM-binding
sites is identical to the σ1 site (56). Autoradiographic
studies have shown that high-affinity DM-binding sites
are distinct from the high-affinity DX-binding site that is
associated with the activated state of the NMDA-receptor
cation channel complex (57). DX has a low affinity for
 Neuromodulations by DM and Its Analogs
DM-binding sites in the brain but is eight times more
potent than DM as a [3H]DX-binding inhibitor (57),
consistent with its higher potency as an NMDA-receptor
antagonist. In addition to σ1-site ligands, a variety of
calcium channel antagonists compete for the σ1 sites that
presumably act as high-affinity DM-binding sites (9),
raising the possibility of an association between DM and
voltage-gated ion channels.
The fact that DM and DX exert biphasic effects on
neural excitation, as exemplified by the observations of
both anti- and proconvulsant effects in the same convul-
sive animals, suggests that these drugs will have only a
narrow therapeutic window in epileptic patients, if they
have any effect at all. Earlier studies have suggested that
epileptogenesis renders the brain more susceptible to the
PCP-like adverse effects of NMDA-receptor antagonists
(58). Many findings are not compatible with the idea that
DM is just a prodrug for DX. Rather, they strongly sug-
gest that the parent drug is primarily responsible for the
anticonvulsant effects observed in vivo, at least in kin-
dling and kainic acid models.
Previous studies have demonstrated that DM prevents
seizures, mortality, and hippocampal cell loss in a dose-
dependent manner (34, 40, 44, 55). One interpretation for
the neuroprotective effects of DM vis-à-vis its anticon-
vulsant effect is that it reduces the excitotoxic effect of
glutamate on neurons by inhibiting NMDA receptors
(59). DM has also been shown to attenuate kainic acid–
induced increases in activator protein-1 (AP-1) binding
activity and c-Jun/Fos–related antigen expression in the
hippocampus, collectively suggesting that DM is an ef-
fective antagonist of kainic acid and a powerful protectant
for convulsants (40, 49).
4.2. Effects on cerebral ischemia
DM treatment has been shown to protect the brain
against infarction and the related pathophysiological and
functional consequences of ischemic injury in several in
vivo ischemia models (60). In addition, several in vitro
(61) and in vivo (62) studies have confirmed the neuro-
protective actions of DM and have offered critical in-
sights into its possible cellular mechanism of action. In
particular, comprehensive studies undertaken with a ro-
dent focal ischemia/reperfusion injury model have shown
that DM has a potent ability to decrease the volume of
cerebral infarction and to improve functional recovery as
post-injury therapy (62).
DM attenuates the loss of vulnerable neurons in the
CA1 region of the hippocampus in global ischemia
models (63) and decreases cerebral infarct size in areas
of severe neocortical damage after ischemia and reperfu-
sion (62). In in vitro hypoxia models, DM reduces neu-
ronal loss and dysfunction, which manifests as a decrease
141
in the amplitude of anoxic depolarization (64). DM also
attenuates the in vitro degeneration induced by acute
glucose deprivation (65).
4.3. Anti-parkinsonian effects
NADPH oxidase, the primary producer of extracellular
superoxide in microglial cells, has been proposed to
contribute to the neurotoxicity of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) (66, 67). In a study of
the mechanisms underlying the neuroprotective activity
of DM, DM was shown to have a significant protective
effect against the dopaminergic toxicity induced by
MPTP (67). Wild-type mice receiving daily MPTP injec-
tions exhibited a significant loss of dopaminergic neurons
in the substantia nigra pars compacta, but DM treatment
significantly attenuated the neuronal loss elicited by
MPTP (67). Relative to the wild-type mice, NADPH
oxidase–deficient mice exhibited a significant resistance
to MPTP-induced DA toxicity (67). In addition, the
neuroprotective effect of DM was observed only in wild-
type mice, but not in NADPH oxidase–deficient mice,
suggesting that NADPH oxidase is a critical target medi-
ating the neuroprotective activity of DM in the MPTP
mouse model.
Observing that MPTP-induced dopaminergic neurode-
generation is associated with reactive microgliosis, Gao
et al. (66) proposed that inhibition of reactive microglio-
sis is the basis for the neuroprotective effect of DM
against MPTP toxicity. In wild-type mice, the initial
dopaminergic neuron-destroying effect of MPTP induces
reactive microgliosis, which in turn activates NADPH
oxidase through the translocation of cytosolic subunits to
the cell membrane and the generation of superoxide. The
neuroprotective effect of DM is attributed to its blockade
of reactive microgliosis induced by DA neuronal death
through the inhibition of both extracellular superoxide
and intracellular reactive oxygen species (67).
In addition, DM blocks the MPTP toxicity–enhancing
effect of the superoxide dismutase inhibitor diethyl-
dithiocarbamate in mice (68). A histological analysis
demonstrated that the depletion of dopaminergic neurons
induced by the co-administration of diethyldithiocarbam-
ate and MPTP is completely prevented by DM. DM also
effectively prevents glutamate toxicity in mesencephalic
cell cultures, as evaluated by the uptake of [3H]-labeled
dopamine. DM shows the same pattern of protection as
nicotine and MK801, both of which increase fibroblastic
growth factor levels in the striatum, suggesting that DM
might also work through a neurotrophic mechanism.
DM has also been found to reverse haloperidol-induced
catalepsy in rats (69) and to potentiate the effect of
levodopa and D1 (but not D2) agonists in reserpine-treated
mice (70). However, conflicting results have been ob-
142 E-J Shin et al
served in human studies (71, 72).
4.4. Effects on pseudobulbar affect
Pseudobulbar affect (PBA), also known as emotional
lability, is characterized by frequent and inappropriate
episodes of crying and/or laughing and is associated with
neurological disorders such as stroke, amyotrophic lateral
sclerosis, Alzheimer’s disease, Parkinson’s disease, and
traumatic brain injury. As PBA has been proposed to
arise (at least in part) from neurochemical dysregulation
of serotonergic, dopaminergic, and/or glutamatergic
neurotransmission (73), agents shown to be useful thera-
peutically against PBA will probably be found to modu-
late this altered state of neurotransmission.
DM is well established as a σ1-receptor agonist that
suppresses the release of excitatory neurotransmitters
(74) and as an uncompetitive antagonist of the NMDA-
sensitive ionotropic glutamate receptor (9). However, its
therapeutic potential is limited by the fact that it is exten-
sively metabolized by cytochrome P450 2D6 to DX,
which is rapidly glucuronidated (6, 75) and unable to
cross the blood-brain barrier (76). Concomitant dosing
with quinidine, one of the most potent inhibitors of cyto-
chrome P450 2D6 activity (77), at 5% – 10% of the anti-
arrhythmic dose increases and sustains the concentration
of DM in plasma, thereby enhancing its potential for
therapeutic efficacy (78).
Although the precise neuroanatomical basis of PBA is
still in question, it is thought to involve the disruption of
inhibitory signals descending from cerebral cortex to
motor regions of the brainstem implicated in the regula-
tion of emotional output (79) Recent evidence suggests
that the severity of cerebellar disconnection is directly
related to PBA onset (80, 81).
Interestingly, neurons in the brainstem and cerebellum
are richly decorated with σ1 receptors, suggesting that the
effect of DM on emotional control is mediated, at least in
part, through its interactions with these receptors. As a
σ1-receptor agonist, DM is expected to inhibit the release
of glutamate, and as an uncompetitive NMDA-receptor
antagonist, it is expected to suppress the response to ex-
citatory neurotransmitters (80). However, the precise
mechanism of action of DM/quinidine in the regulation
of PBA remains uncertain.
The above findings expand the recent clinical evidence
that DM/quinidine co-administration markedly reduces
PBA frequency and severity with satisfactory safety and
high tolerability, increasing patient quality-of-life (81).
4.5. Effects on pain sensation
NMDA can cause somatic and neuropathic pain. Upon
tissue injury, pain transmission passes through Aδ- and
C-sensory fibers to the dorsal horn neurons, causing the
release of peptides and excitatory amino acids and acti-
vating NMDA receptors (82, 83). This hyperexcitability
event can prolong and intensify the sensation of pain.
Although not widely used today as an analgesic, DM
was initially considered a pharmacologic alternative to
morphine for pain management (84). DM modulates the
sensation of pain by reducing the excitatory transmission
of the primary afferent pathways along the spinothalamic
tract. This process occurs in the dorsal horn of the spinal
cord, where DM blocks NMDA receptors, reducing the
threshold for pain transmission via the Aδ- and C-sensory
fibers (85). The activation of neuronal firing by NMDA
receptors increases intracellular calcium levels (86). DM
has been shown to reduce and regulate the influx of in-
tracellular calcium through NMDA receptor–gated
channels (87), thereby antagonizing the effects of excit-
atory amino acids and reducing the release of various
peptides, such as glutamate and aspartate. Thus, it can
ultimately lead to an overall reduction of pain sensation
(83).
NMDA-receptor antagonists have been found to pre-
vent the induction of central sensitization under experi-
mental conditions (85). These preclinical observations
have led to the hypothesis that NMDA antagonists might
reduce postoperative pain (85). In fact, pretreatment with
DM effectively reduces postoperative pain after tonsil-
lectomy, and the pain is reduced not only at rest but also
on swallowing, suggesting that DM prevents the develop-
ment of central sensitization after tonsillectomy (88).
5. Neuroprotective effects of DM analogs with im-
proved safety profiles
5.1. Neuroprotective potential of DF
Dimemorfan (DF, 3-methyl-17-methylmorphinan), an
effective non-narcotic antitussive agent with a low inci-
dence of adverse events (89), was discovered through
extensive screening of morphinan analogs and was first
used in Japan in 1975 (89, 90). Its antitussive action ap-
pears to arise from a direct effect on the cough center in
the medulla. It does not induce any significant physical
or psychological dependence (89), and its antitussive
action is not affected by the opioid receptor–blocker
levallorphan. Studies in animal models indicate that DF
is up to three times more potent as an antitussive agent
than codeine and is equivalent in potency to DM. Its
other possible beneficial effects have been evaluated
using diverse models of neurodegeneration. Interestingly,
the evidence indicates that the recognition sites for DM
and DF are identical or overlapping (55, 91).
Previous studies demonstrated that DF is a high-affinity
ligand for the σ1 receptor (Ki = 151 nM) but not the PCP
site (Ki = 16798 nM) and has anticonvulsant properties
 Neuromodulations by DM and Its Analogs
(43, 55, 91). In addition, it has been reported to activate
σ1 receptors to attenuate scopolamine- and β-amyloid
peptide–induced amnesia in mice (92), possibly through
its enhancement of hippocampal acetylcholine release
(93). Our group has reported that the anticonvulsant ef-
fect of DF correlates with its σ1-receptor–activated modu-
lation of the AP-1 transcription factor (43, 55). Similarly,
DF exhibits a protective effect against cerebral ischemia–
reperfusion injury in rats through a σ1-receptor–dependent
mechanism that blocks glutamate accumulation and the
downstream pathologic events that cause ischemic brain
injury (94). In contrast, DF acts via σ1-receptor–
independent mechanisms to modulate intracellular cal-
cium release, NADPH oxidase activity, and NF-κB sig-
naling, inhibiting the expression of inducible nitric oxide
(NO) synthase and the production of NO and pro-inflam-
matory cytokines. These activities may contribute to its
anti-inflammatory properties and its protective effects
against endotoxin shock in mice (95).
5.2. Anticonvulsant effects of other DM analogs
Some newly developed DM analogs have also shown
promising anticonvulsant effects (20, 34, 96). In investi-
gating the effects of a series of synthetic DM analogs
(modified at positions 3 and 17 of the morphinan ring
system: see Fig. 1) on maximal electroshock convulsions
in mice, Kim et al. (34) found that DM, DX, 3-allyloxy-
17-methylmorphinan (3-AM), and 3-cyclopropylmethox
y-17-methylmorphinan (3-CM) had anticonvulsant ef-
fects, whereas 3-methoxymorphinan and 3-HM did not.
According to these studies (20, 34, 96), DM, DX, 3-AM,
and 3-CM have high-affinity for σ1 receptors, but all have
low affinity for σ2 receptors. In binding to PCP sites, DX
has a higher affinity than DM, whereas 3-AM and 3-CM
have very low affinities, suggesting that PCP sites are not
required for the anticonvulsant actions of 3-AM and
3-CM (34). These studies show that these new DM ana-
logs are promising anticonvulsants that are devoid of
PCP-like behavioral side effects and that their anticon-
vulsant actions may be, at least in part, mediated via σ1
receptors (34, 55, 97).
5.3. Anti-parkinsonian effect of 3-HM
In structure–activity studies designed to find more
potent neuroprotective DM analogs, 3-HM, a DM me-
tabolite lacking methyl groups at the O and N sites,
emerged as a novel candidate for the treatment of
Parkinson’s disease (98). Zhang et al. showed that 3-HM
is a more potent neuroprotective agent than its parent
compound, DM, against lipopolysaccharide (LPS)-
induced neurotoxicity and that it is neurotrophic to do-
paminergic neurons in primary mixed mesencephalic
neuron–glial cell cultures (98, 99). Furthermore, after
143
showing that the neurotrophic effect of 3-HM is glial
cell–dependent and that 3-HM fails to show any protec-
tive effect in neuron-enriched cultures, they subsequently
demonstrated that it is the astroglial cells, and not the
microglial cells, that contribute to the neurotrophic effect
of 3-HM (98). This conclusion was based on reconstitu-
tion studies in which microglial or astroglial cells were
added back to neuron-enriched cultures at various final
percentages (10% – 20% and 40% – 50%, respectively);
3-HM was neurotrophic after the addition of astroglial
cells but not microglial cells (98).
Conditioned medium from 3-HM–treated astroglial
cells exerts a significant neurotrophic effect on dopami-
nergic neurons. 3-HM appears to induce the astroglia to
release certain neurotrophic factors (i.e., epidermal
growth factor, glial cell-derived neurotrophic factor,
transforming growth factor-β1 and -α1, and activity-
dependent neurotrophic factor) (98) that are responsible
for its neurotrophic effects. As might be expected, in
addition to the detrimental effect of Parkinson’s disease
on DA neurons, a considerable glial reaction that is po-
tentially protective takes place in the substantia nigra
pars compacta in Parkinson’s disease. The glial cells
(particularly the astroglia) protect stressed dopaminergic
neurons by producing neurotrophic factors that counter-
act oxidative stress. One potential therapeutic avenue for
Parkinson’s disease would be the stimulation of astroglial
cells to produce these neurotrophic factors to rescue
damaged or dying neurons.
In addition to its neurotrophic effect, 3-HM has an
anti-inflammatory mechanism that is also important for
its neuroprotective activity; in the reconstitution experi-
ments of Zhang et al., LPS-induced neurotoxicity and
3-HM-mediated neuroprotection increased as the per-
centage of microglial cells added back to the neuron-
enriched cultures increased (98). 3-HM provides potent
neuroprotection by acting on two different cell targets: it
has a neurotrophic effect mediated by astroglial cells and
an anti-inflammatory effect mediated by inhibition of
microglial cell activation. The higher potency of 3-HM
relative to DM is attributable to the neurotrophic effect
that occurs in addition to the anti-inflammatory effect
shared by both substances (97, 98).
Zhang et al. (98) also observed a neuroprotective effect
for 3-HM in both in vivo and in vitro studies using the
MPTP model. In their in vitro system using primary
mixed mesencephalic neuron–glial cell cultures, 3-HM
(1 – 5 μM) significantly and dose-dependently attenuated
the reduction in dopamine uptake induced by MPTP or
its active component, 1-methyl-4-phenylpyridinium
(MPP+). At the same concentrations, 3-HM also signifi-
cantly increased the dopamine uptake capacity of the
cells, confirming its neurotrophic effect. In their in vivo
144 E-J Shin et al

studies, the administration of 3-HM significantly reduced
the MPTP-induced loss of nigral dopaminergic neurons,
as previously seen for DM. Significant depletion of dop-
amine and its metabolites 3,4-dihydroxyphenylacetic
acid and homovanillic acid is observed in the striata of
MPTP-treated mice, and levels of all of these biogenic
amines are attenuated in lesioned mice previously treated
with 3-HM. The advantage of 3-HM over DM is the
neurotrophic effect of the former, which may enhance
the sprouting of dopaminergic terminal fibers in the stria-
tum, accelerate the formation of dopamine-containing
vesicles, assist the re-synthesis of dopamine after lesions,
and eventually re-establish the return of the DA system
to normal functioning. In addition, the anti-inflammatory
effect exerted by 3-HM resulting from the inhibition of
microgliosis generated from the MPTP/MPP+-damaged
dopaminergic neurons is another important mechanism
of 3-HM. 3-HM inhibits the reactive microgliosis in
primary mesencephalic neuron–glial cells cultures after
MPTP/MPP+ treatment (98).
Thus, in in vivo and in vitro MPTP models of Parkin-
son’s disease, 3-HM is beneficial both in reducing do-
paminergic neuronal degeneration in the substantia nigra
pars compacta and in reversing the depletion of biogenic
amines in the striatum through dual mechanisms —a
neurotrophic effect and the reduction of reactive micro-
gliosis— consequently providing significant neuropro-
tection.
5.4. Anti-parkinsonian effect of GCC1290K, a 3-HM
prodrug
To enhance the oral bioavailability of 3-HM, which is
approximately 18%, we synthesized the 3-HM prodrug
GCC1290K (Fig. 1), which has a much higher oral bio-
availability of approximately 92%. The anti-parkinsonian
effects produced by i.p. administration of 3-HM are
comparable to those produced by oral administration of
GCC1290K (data not shown). These findings are de-
scribed in our PCT patent application WO/2008/111767A1
[“Orally bioavailable prodrug of (+)-3-hydroxymorph-

Altered receptor modulation in NMDA-/ 1-/

PCP-receptors Production of psychotoxicity
including cognitive dysfunction

DM
PCP Psychotoxic
DX binding site effects
(major
metabolite
of DM)
3-AM &
DF 3-HM (or GCC1290K)
3-CM

1 NMDA L-type Anti-

receptor receptor calcium inflammation/
channel Antioxidant/
Neurotrophic
effect

Anti-ischemic effect and Anti-convulsive

alleviation of effect
pseudobulbar affect Anti-parkinsonian
effect Fig. 3. Neuropharmacological actions mediated
Analgesic effect by DM and DM analogs. DM=dextromethorphan,
DX=dextrorphan, DF=dimemorfan, 3-HM=3-hy-
3-AM, 3-CM, DF, and 3-HM (or GCC1290K) exert their droxymorphinan, 3-AM=3-allyloxy-17-methyl-
neuroprotective effects with satisfactory behavioral morphinan, 3-CM=3-cyclopropylmethoxy-17-
methylmorphinan, PCP=phencyclidine, NMDA=
safety.
N-methyl-D-aspartate.
 Neuromodulations by DM and Its Analogs 145

Table 1. Neuropsychopharmacological profiles of DM and its analogs

3-HM
DM DX DF 3-MM 3-AM 3-CM
(GCC1290K)
Neuropharmacological properties
DM binding site +++ 57 + 57 ND ND ND ND ND
97
DX binding site + +++ 97 – 97 – 97 – 97 – 97 – 97
PCP binding site + 34, 44 +++ 34 – 55, 91 – – – 34 – 34
σ1 binding site +++ 34, 44, 47, 55, 91 +/++ 34, 44, 47, 55, 91 +++ 55, 91 ND ND +++ 34 +++ 34
Antagonism of
+ 9, 59 +/++ 9, 59 ND ND ND ND ND
NMDA receptor
Blockade of L-type
+++ 42 + 42 +++ 43 ND ND ND ND
calcium channel
Neuropsychotoxicities (with high dose)
PCP-like behavior ++ 10, 13, 34, 98 +++ 14, 34, 98 – 98 – 34, 98 – 34, 98 – 34, 98 – 34, 98
Cognitive dysfunction ++ 29, 31, 33 +++ 30, 32 ND ND ND ND ND
Neuroprotections
Anticonvulsant effect +++ 34-44 +++ 34, 36, 42 ++ 43, 55 – 34 – 34 ++ 34 ++ 34
Anti-ischemic effect +++ 60, 62, 63 +++ 100 ++ 94 ND ND ND ND
67, 98 98 98, 99 98
Anti-parkinsonian effect +++ ND – +++ ND – + 98
81
Palliation of PBA syndrome ++ ND ND ND ND ND ND
84, 88
Analgesic effect ++ ND ND ND ND ND ND
+++: high, ++: moderate, +: low, –: negligible, ND: non-determined. Each superscript indicates cited reference number.

inan for Parkinson’s disease prevention or treatment”].
An Investigational New Drug Application for the prodrug
(IND 107,477) has been approved by the United States
Food and Drug Administration. GCC1290K is totally
free from safety issues, as shown by studies using 3-HM
(data not shown) and is now undergoing clinical trials.
5.5. Behavioral effects of DM analogs
The repeated administration of DM or its major me-
tabolite, PCP-like DX, significantly increases locomotor
activity and circling behavior, although these behavioral
responses are less pronounced than those caused by PCP.
These behavioral responses are enhanced much less by
DF and 3-HM (or GCC1290K) than by DM and DX. In
terms of behavioral effects, DM, DX, and PCP produce
significant behavioral side effects (i.e., CPP and locomo-
tor stimulation), but DF and 3-HM (or GCC1290K)
produce very few behavioral side effects (as seen in DM-
or DX-treated animals), suggesting that DF and 3-HM
have negligible psychotropic effects (34, 97, 98).
6. Conclusions
The research findings discussed in this review demon-
strate that DM produces neuropsychotoxic effects and
has a potential for abuse, although it also has diverse
positive effects. In addition, the evidence suggests that
DM and its analogs offer strong neuroprotective benefits
in multiple neurodegenerative disorders through their
antioxidant, anti-inflammatory, and neurotrophic effects
and through their modulation of the interactions between
NMDA, PCP, and σ1 receptors (refer to Fig. 3 and Table
1). Thus, they offer a promising new direction for the
development of therapeutic compounds for the treatment
of excitotoxic and inflammatory neurodegenerative
disorders.
Acknowledgments
This study was supported by a grant from the Brain Research
Center from 21st Century Frontier Research Program funded by the
Ministry of Science and Technology, Republic of Korea; by a grant
(#A101069) of the Korea Healthcare Technology R&D project,
Ministry of Health & Welfare, Republic of Korea; and by a grant
(#E00025) of the Korea-Japan Joint Research Program, National Re-
search Foundation of Korea, Republic of Korea. Jae-Hyung Bach was
supported by the BK 21 program. This work was, in part, supported
by grants of the Research on Risk of Chemical Substances, Ministry
of Health Labour, and Welfare and the Academic Frontier Project for
Private Universities, Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
146 E-J Shin et al
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