Synthesis and study the analgesic effects of new analogues of ketamine on female wistar rats

Article abstract of DOI:10.2174/157340612800493683

Ketamine (2-o-chlorophenyl-2-methylaminocyclohexan, CAS 1867-66-9, CI-581, Ketalar, I), a potent derivative of Phencyclidine (1-[1-phenylcyclohexyl] piperidine, CAS 956-90-1, PCP, II), and many of its analogues have shown anesthetic and analgesic effects. In this research, new derivatives of I, (2-[p-methoxybenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-OCH ₃, III), (2-[p-methylbenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-CH₃, IV) and their intermediates (V-VIIII) were synthesized and the acute and chronic pains of III and IV were evaluated on rats using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests. The results werecompared with ketamine and control (saline) groups. The results indicated that in tail immersion and formalin tests, these new derivatives (III and IV) were usually effective for decreasing pain on rats.

Full text of DOI:10.2174/157340612800493683

246
Medicinal Chemistry, 2012, 8, 246-251
Synthesis and Study the Analgesic Effects of New Analogues of Ketamine
on Female Wistar Rats
Abbas Ahmadi*1, Mohsen Khalili2, Ramin Hajikhani3, Horiesadat Hosseini1, Nasrin Afshin1, Babak
Nahri-Niknafs4
1Department of Chemistry, Faculty of Science, Islamic Azad University, Karaj branch, Karaj, Iran
2Department of Physiology, Shahed University, Tehran, Iran
3Department of Physiology, Islamic Azad University, Karaj branch, Karaj, Iran
4Islamic Azad University, Karaj branch, Karaj, Iran
Abstract: Ketamine (2-o-chlorophenyl-2-methylaminocyclohexan, CAS 1867-66-9, CI-581, Ketalar, I), a potent deriva-
tive of Phencyclidine (1-[1-phenylcyclohexyl] piperidine, CAS 956-90-1, PCP, II), and many of its analogues have shown
anesthetic and analgesic effects. In this research, new derivatives of I, (2-[p-methoxybenzylamino]-2-[p-methoxyphenyl]
cyclohexanone, ket-OCH3, III), (2-[p-methylbenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-CH3, IV) and their
intermediates (V-VIIII) were synthesized and the acute and chronic pains of III and IV were evaluated on rats using tail
immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests. The re-
sults werecompared with ketamine and control (saline) groups. The results indicated that in tail immersion and formalin
tests, these new derivatives (III and IV) were usually effective for decreasing pain on rats.
Keywords: Acute and chronic pains, analgesic effects, CAS 1867-66-9, CAS 956-90-1, formalin test, new derivatives of keta-
mine, tail immersion test.
INTRODUCTION
In this work, two new ketamine derivatives (III and IV)
were synthesized and the analgesic effects of these com-
pounds were evaluated on rats using tail immersion (as a
model of acute thermal pain) and formalin (as a model of
acute chemical and chronic pain) tests whereas the results
were compared with ketamine (I) and control (saline)
groups.
Ketamine (2-o-chlorophenyl-2-methylaminocyclohexan,
CAS 1867-66-9, CI-581, Ketalar, I, Scheme 1) was origi-
nally synthesized and developed by Park-Davis Companyin
1962. It is
a
Phencyclidine (1-[1-phenylcyclohexyl]
piperidine, CAS 956-90-1, PCP, II, Scheme 1], derivative
that produces anesthesia and analgesia similar to PCP, but
generates a shorter duration of action and less propensity to
produce convulsions [1-3]. A dissociative anesthetic with
complex actions on central nervous system (CNS), ketamine
acts as a non-competive antagonist of glutamate N-methyl-
D-asparate (NMDA) receptor. It also shows other complex
effects on the CNS [4]. Ketamine interacts with multiple
binding sites (NMDA and non-NMDA glutamate receptors,
nicotinic and muscarinic cholinergic receptors,adrenergic
and opioid receptors), however, it is generally believed that
NMDA receptor antagonism accounts mostly for its anes-
thetic and partly for analgesic effects, whereas some of its
analgesic effects are mediated through its agonistic effects at
opioid receptors within the central nervous system [5].So far,
some of the derivatives of ketamine have been synthesized
[6-10] and the pharmacological activities, such as respiratory
depression and antinociception [5], acute and chronic pain
[11] analgesic effects [12-18] have been studied.
MATERIAL AND METHODS
General
All chemicals, including cyclopentyl bromide, 4-methoxy
benzonitrile, bromine, 4-methyl benzylamine, 4-methoxy
benzylamine, magnesium turnings and diethyl ether were
purchased from Merck Chemical Co. (Darmstadt, Germany).
Melting points (uncorrected) were determined using a digital
Electro Thermal Melting Point apparatus (model 9100, Elec-
1
trothermal Engineering Ltd., Essex, UK). H and13C NMR
spectra were recorded on a Bruker 300 MHz (AMX model,
Karlsruhe, Germany) spectrometer (internal reference:
TMS). IR spectra were recorded on a Thermo Nicolet FT-IR
(Nexus-870 model, Nicolet Instrument Corp, Madison, Wis-
consin, U.S.A.) spectrophotometer. Mass spectra were re-
corded using Agilent Technologies 5973, Mass Selective
Detector (MSD) spectrometer (Wilmington, USA). Column
chromatographic separations were performed over Acros
silica gel (No.7631-86-9 particle size 35-70 micrometer,
Geel, Belgium). Female Wistar rats (at Pasteur's Institute,
Tehran, Iran), ranging from175g to 230g of weight, were
used for pharmacological testing.
*Address correspondence to this authors at the Department of Chemistry,
Faculty of Science, Islamic Azad University, P.O.Box: 31485-313, Karaj,
Iran; Tel: +98261-4403145; Fax: +98261-4403125;
E-mail: a-ahmadi@kiau.ac.ir
1875-6638/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of New Analgesic Analogues of Ketamine
Medicinal Chemistry, 2012, Vol. 8, No. 2 247
O
OCH3
NHCH3
N
NH
O
H2C
Cl
I
III
OCH3
II
OCH3
O
O
NH
H2C
Br
O
H3CO
H3CO
VI
VII
IV
CH3
H2C
N
CH3
H2C
OCH3
N
HO
HO
H3CO
H3CO
VIIII
VIII
Scheme 1. Structure formulas of Ketamine (I), Phencyclidine (II), Ket-OCH3 (III), Ket-CH3 (IV),p-methoxyphenylcyclopenthyl ketone
(VI), 1-Bromocyclopenthyl-(p –methoxyphenyl) ketone(VII), 1-(ꢀ-p-methoxybenzylimino) (p-methoxybenzyl) cyclopentanol (VIII) and 1-
(ꢀ-p-methoxybenzylimino) (p-methoxybenzyl) cyclopentanol (VIIII).
Preparations (Scheme 2)
114.8, 131.1, 131.3, 132.9, 158.8, 163.2, 164.4.MS: m/z
(regulatory intensity): 339 (11).
Cyclopenthyl magnesium bromide, V
1-(ꢀ-p-methylbenzylimino) (p-methoxyphenyl) cyclopenta-
nol (VIIII)
This compound was prepared from Cyclopenthyl bro-
mide and magnesium in diethyl ether following a published
method [19].
A solution containing 8.2 g of bromo ketone (VII) in
50ml of benzene and 20g (0.16 mol) of p-methyl benzy-
lamine was stirred in room temperature for 7 days. Then, n-
pentane was added and the reaction mixture was filtered,
evaporated and concentrated. The obtained brown oily resi-
due was passed through a silica gel column using ethyl ace-
tate-hexane as the eluent to afford 4.97g of VIIII (41 %
yield).
p-methoxyphenylcyclopenthyl ketone (VI)
This compound was prepared at 64% yield from cy-
clopenthyl magnesium bromide (V) and p-methoxyben-
zonitrile according following a known procedure [19].
1-Bromocyclopenthyl-(p-methoxyphenyl) ketone (VII)
This compound was prepared at 58% yield from VI and
bromine in carbon tetrachloride at 0°C following a published
method [20].
IR (KBr): 3380, 3329, 2873, 1619, 1563, 1439, 1333,
1021, 812 cm-1.1H N.M.R. (CDCl3) (p.p.m.): 0.94-1.34 (8H,
m), 2.02 (1H, m), 2.32 (3H, s), 4.49 (2H, s), 6.92-7.75 (8H,
m).13C N.M.R. (CDCl3) (p.p.m.): 23.1, 24.8, 37.7, 56.2, 59.4,
79.8, 114.8, 129.2, 131.3, 132.9, 133.9, 136.2, 163.2,
164.4.MS: m/z (regulatory intensity): 323 (11).
1-(ꢀ-p-methoxybenzylimino) (p-methoxybenzyl) cyclopen-
tanol (VIII)
A solution containing 8.2g of bromo ketone (VII) in 30
ml benzene and 20g (0.15 mol) of p-methoxybenzylamine
was stirred in room temperature for 5 days. Then, n-pentane
was added and the reaction mixture was filtered, evaporated
and concentrated. The obtained brown oily residue was
passed through a silica gel column using ethyl acetate-
hexane as the eluent to afford 6g of VIII (57 % yield).
2-(p-methoxybenzylamino)-2-(p-methoxyphenyl) cyclohex-
anone (Ket-OCH3) (III)
A solution containing 6 g of VIII in 30 ml of decaline re-
fluxed for 4 hours in 190°C. Then the reaction mixture was
extracted with diethyl ether. The organic layer was separated
and water-washed and the base was neutralized with 10%
H2SO4, washed with 20% NaOH, re-extracted with n-
Hexane, dried and concentrated. The obtained oily residue
was passed through a silica gel column using ethyl acetate-
hexane as the eluent to obtain 3.25g of III (54 % yield). The
IR (KBr): 3430, 2933, 1708, 1608, 1512, 1437, 1248,
1032 cm-1.1H N.M.R. (CDCl3) (p.p.m.): 0.92-1.48 (8H, m),
2.02 (1H, m), 3.76 (6H, s), 4.46 (2H, s), 6.52-7.75 (8H,
m).13C N.M.R. (CDCl3) (p.p.m.): 23.1, 37.7, 56.2, 59.4, 79.8,

248 Medicinal Chemistry, 2012, Vol. 8, No. 2
Ahmadi et al.
MgBr
Br
NC
OCH3
Mg / I2
VI
Diethyl ether
V
Br2 / CCl4
CH2
NH2
OCH3
Decaline
Reflux
III
VII
VIII
Benzene
CH2
NH2
CH3
Benzene
Decaline
Reflux
VIIII
IV
Scheme 2. Synthesis of intermediates (V-VIIII) and final compounds (III and IV).
hydrochloride salt of III (m.p.133-136°C, red brownish
solid) was prepared using 2-propanol and HCl, and recrystal-
lized from 2-propanol.
light/dark cycles. Rats were given free access to water and
standard laboratory rat chow (supplied by Pars Company,
Tehran, Iran). All behavioral experiments were carried out
between 11 a.m. and 4 p.m. under normal room light and at
25oC. All the animals were injected by a researcher, and
evaluated by another. This study was carried out according
to the Guides for the “Care and Use of Laboratory Animals”
(NIH) and those of the “Research Council of Shahed Univer-
sity of Medical Sciences, Tehran, Iran”.
IR (KBr): 3383, 3324, 2920, 1615, 1515, 1475, 1382,
1072, 801 cm-1.
1H N.M.R. (CDCl3) (p.p.m.): 0.89-1.30 (8H, m), 2.01
(1H, m), 3.79 (6H, s), 3.90 (2H, s), 6.90-7.63 (8H, m).13C
N.M.R. (CDCl3) (p.p.m.): 23.1, 25.03, 35.82, 37.54, 55.6,
64.8, 77.7, 114.3, 128.8, 132.1, 158.7, 161.4, 207.4.MS: m/z
(regulatory intensity): 339 (12).
Tail Immersion Test
2-(p-methylbenzylamino)-2-(p-methoxyphenyl) cyclohex-
anone (KET-CH3) (IV)
The acute thermal pain was modeled by the tail immer-
sion test [21, 22]. Twenty minutes after an intraperitoneal
injection of drugs (ketamine and its analogues, 6mg/kg) or
an equivalent volume of saline (control), the rats (n = 8 in
each group) were housed in an animal restrainer. Then, the
terminal 5cm of their tails was first submerged into room
temperature water (22~24 °C) to check their aversion to wa-
ter and then immersed in 52 °C water. The reaction time be-
tween immersing the tail and its removal from heated water
was measured. Cut-off latency in 15s was employed to avoid
damaging the tail.
A solution containing 5g of VIIII in 30ml of decaline
was refluxed for 5 hours in 190°C. Then the reaction mixture
was extracted with diethyl ether. The organic layer was sepa-
rated, water-washed and the base was neutralized with 10%
H2SO4, washed with 20% NaOH, re-extracted with n-
Hexane, and it was dried and concentrated. The oily residue
obtained, was passed through a silica gel column using ethyl
acetate-hexane as the eluent to afford 1.5g of IV (30 %
yield).
The hydrochloride salt of IV (m.p. 129-130°C, black
solid) was prepared using 2-propanol and HCl and it was re-
crystallized from 2-propanol.
Formalin Test
The Formalin test was introduced by Dubuisson and
Dennis [23]. In this test, the formaldehyde solution (50 ꢀl,
2.5%) was injected subcutaneously into the plantar surface
of the hind paw. Then the animal was placed in a Plexiglas
chamber (30ꢁ30ꢁ30 cm3) mirrored at 45o angle underneath
for accurate observation. In the treatment groups, the drugs
(ketamine and its analogues) were administered intraperito-
neally 30 minutes prior to the formaldehyde injection. Prior
to the experiments, all animals were brought to the test
chamber five times at five-minute-intervals in order to adapt
them to the environment. The behavioral pain reactions due
to formalin injection were detected and recorded for 1 hour.
The first 15 minutes after formalin injection was known as
the early (I) or acute phase and the period between 15-60
IR (KBr): 3418, 2922, 1687, 1603, 1513, 1450, 1257,
1021 cm-1.
1H N.M.R. (CDCl3) (p.p.m.): 0.86-1.96 (8H, m), 2.03
(1H, m), 2.30 (3H, s), 3.79 (3H, s), 3.84 (2H, s), 6.92-7.58
(8H, m).13C N.M.R. (CDCl3) (p.p.m.): 19.7, 25.2, 26.7, 32.7,
37.1, 48.9, 55.7, 76.6, 114.7, 129.2, 129.7, 133.9, 162.8,
208.4.MS: m/z (regulatory intensity): 323 (12).
Pharmacological Methods
Female Wistar rats (Pasteur’s Institute, Tehran, Iran),
weighing 175-230g, were randomly housed in a group of
four per cage in a temperature-controlled colony room under

Synthesis of New Analgesic Analogues of Ketamine
Medicinal Chemistry, 2012, Vol. 8, No. 2 249
6
5
4
3
2
1
0
Control
Ketamine
Ketamine-CH3
Ketamine-OCH3
2
5
10
15
20
25
30
35
40
45
Time (min)
Fig. (1). Mean tail immersion latency (s) in animals receiving Ketamine (I), Ket-OCH3 (III),Ket-CH3 (IV) hydrochloride or saline (control)
in doses of 6 mg/kg. The tail immersion test was conducted 20 minutes after the drug injection. Each point represents the mean ± S.E.M. of
tail immersion latency (s) in 8 animals.
The analgesic activity of ketamine (I), 2-(p-methoxybenzyl-
amino)-2-(p-methoxyphenyl) cyclohexanone (ket-OCH3,
III) hydrochloride with Tail Immersion Test
minutes known as the second (II) or chronic phase. How-
ever, the chronic phase could be divided into initial (15-40
min.) and late (40-60 min.) periods.
Intraperitoneal injection of ketamine (I) and 2-(p-
methoxybenzylamino)-2-(p-methoxyphenyl) cyclohexanone
(ket-OCH3, III) hydrochloridein dose of 6mg/kg generated
analgesic effects in tail immersion test (as a model of acute
thermal pain). As indicated in Fig. (1), both compounds
(ketamine and its newly synthesized derivative) could pro-
duce apparently identical analgesic effects in tail immersion
test, comparing to control group, especially in 5-25 minutes
after the drugs injection. However, a mild but non- signifi-
cant difference between analgesic effects of I and III in 5-10
and 25-45 minutes after the drugs application was observed.
The difference in the tail immersion latencies was evaluated
using method ofanalysis of variances (ANOVA).
RESULTS
Chemistry
Ketamine (I) and its newly synthesized derivatives (III
and IVI) were synthesized by reaction of cyclopenthyl mag-
nesium bromide (Grignard reagent, V) with substituted ben-
zonitriles (chlorine, p-methoxy and p-methyl) compounds.
To reach more electron distribution and dipole moments, a
methoxy group was substituted in the phenyl ring [24]. Addi-
tionally, benzylamines with electron donating groups [24]
(III and IV) were caused that the nonbonding nitrogen elec-
trons of the amine group would be more active comparing to
methylamine in ketamine. The known procedures were ap-
plied to synthesize the compounds V-VII [19, 20]. Spectro-
scopic data (IR, 1H and 13C NMR, Mass) confirmed the
structure of the newly synthesized compounds (III, IV, VIII,
and VIIII). The purity of each compound was checked by
TLC using ethyl acetate-hexane as the eluent.
The analgesic activity of ketamine (I), 2-(p-methylbenzyl-
amino)-2-(p-methoxyphenyl) cyclohexanone (ket-CH3, IV)
hydrochloride with Tail Immersion Test
Intraperitoneal injection of ketamine (I) and 2-(p-
methylbenzylamino)-2-(p-methoxyphenyl) cyclohexanone
(ket-CH3, IV) hydrochloridein dose of 6mg/kg generated
analgesic effects in tail immersion test (as a model of acute
thermal pain). As indicated in Fig. (1), both compounds (I
and IV) could produce apparently identical analgesic effects
in tail immersion test, comparing to control group, especially
in15-25 minutes after the drugs injection. However, a mild
but non-significant difference between analgesic effects of
these compounds (I and IV) in 25-45 minutes after the drugs
application was observed. The difference in the tail immer-
sion latencies was evaluated using method of analysis of
variances (ANOVA).
Pharmacology
General Consideration
Mortality (number of death), morbidity (an abnormal
condition or behavior due to a disorder), irritability (a condi-
tion of aggressiveness or increased response on handling)
and other related abnormal states were observed in the ex-
perimental animals. The motor coordination index (measured
by Rota-rod apparatus, Harvard, UK) did not indicate any
significant differences between control and treated rats.

250 Medicinal Chemistry, 2012, Vol. 8, No. 2
Ahmadi et al.
Control
3
2.5
2
Ketamine
Ket-CH3
Ket-OCH3
*$
*$
*#
*
*
*
*
*
1.5
*
1
0.5
0
Phase I
Initial phase II
Late phase II
Fig. (2). Comparison between the acute and chronic formalin pains in Ketamine (I), Ket-OCH3 (III), Ket-CH3 (IV) hydrochloride or saline
(control)in doses of 6 mg/kg. Data show the mean ±S.E.M of pain score. n=8, * p<0.05, *** p<0.001 when compared with control and $
p<0.05 when compared with Ketamine group.
The analgesic activity of ketamine (I) and 2-(p-
methoxybenzylamino)-2-(p-methoxyphenyl) cyclohexanone
(ket-OCH3, III) hydrochloride with Formalin Test
kapa and delta receptors [27]. In this research, two new keta-
mine derivatives were synthesized with substitution changes
in phenyl (p-methoxyphenyl), amine (p-methoxybenzylamin,
III and p-methylbenzylamin, IV) groups. Stated in our
previous work, substitutingmethyl and methoxy groups (high
electron donating groups with more electron distributions
and dipole moments) in PCP (a well-known ketamine
derivative) generated stronger analgesic effects [24, 28]. To
have some pharmacological effects of benzylamine
derivatives, such newly developed changes were selected in
our recent work. Results indicated that in tail immersion test,
these new derivatives (III and IV) could be effective more
frequently in decreasing pain, comparing to control group.
Also lower anti-nociception effects were observed in tail
immersion test in 5, 10 and 25 minutes for III; 15, 20 and 25
minutes for IV; 2, 5, 10, 25 and 35-45 minutes for ketamine
after injection, comparing to control group. In formalin test,
the results showed that the new derivatives (III and IV) and
ketamine (I) exhibited significant but apparently identical
effects on acute chemical pain, comparing to control group.
However, chronic pain (phase I and II) could be significantly
attenuated with new compounds (III and IV), comparing to
control group.
The drugs (I and III) were intraperitoneally injected in
dose of 6 mg/kg, 30 minutes before the formaldehyde injec-
tion. Results showed that both compounds (I and III) have
significant and similar effects on acute formalin chemical
pain (as a model of acute chemical and chronic pain) (Fig. 2)
comparing to control group. However, chronic formalin pain
(phase I and II) could significantly attenuate with these com-
pounds (I and III), comparing to control group. The differ-
ence in the pain scores was evaluated using method of analy-
sis of variances (ANOVA).
The analgesic activity of ketamine (I) and 2-(p-
methylbenzylamino)-2-(p-methoxyphenyl) cyclohexanone
(ket-CH3, IV) hydrochloride with Formalin Test
The drugs (I and IV) were intraperitoneally injected in
dose of 6mg/kg, 30 minutes before the formaldehyde injec-
tion. Results showed that both compounds (I and IV) have a
significant and similar effects on acute formalin chemical
pain (as a model of acute and chronic chemical pain) (Fig. 2)
comparing to control group. However, chronic formalin pain
(phase I and II) could be significantly attenuate with these
compounds (I and IV), comparing to control group. The dif-
ference in the pain scores was evaluated using method of
analysis of variances (ANOVA).
It was concluded that such changes on ketamine structure
might decrease their half-life by higher conjugations in liver
or excretions in kidney. The structural disturbance due to
these changes might be considered as another cause for their
semi-agonistic effects on ketamine receptors. Furthermore,
as ketamine mainly produces analgesic effects through its
receptors in central nervous system (CNS), it might be con-
cluded that the newly synthesized compounds could not eas-
ily be transferred from blood brain barriers as efficiently as
ketamine.
DISCUSSION
The analgesic effect of ketamine was first described by
Domino and collaborators [1]. This compound in low sub-
anesthetic dosage was considered a reliable analgesic in
acute pain [21] acting more selectively as a non-competitive
blocker of the NMDA receptor to the PCP recognition site
[25]. The analgesic effect of ketamine occurs concentrated
within its PCP site occupancy range [26], but at higher con-
centration, ketamine interacts with sigma sites and opioid,
CONCLUSION
Introducing a methoxy group with a high electron dona-
tion and dipole moment to phenyl ring, and swapping methy-

Synthesis of New Analgesic Analogues of Ketamine
Medicinal Chemistry, 2012, Vol. 8, No. 2 251
[13]
[14]
Elstrate, A.C.V.; Lebrun, T.; Sandefo, I. Are preemptive analgesic
effects of ketamine linked to inadequate perioperative analgesia?
AnesthAnalg, 2004, 99, 1576-1582.
Yamauchi, M.; Asano, M.; Watanabe, M. Continious low-dose
ketamine improves the analgesic effects of fentanyl patient-
controlled analgesia after cervical spine surgery. International
Anesth. Res. Soc. 2008, 107(3), 1041-1044.
lamine with methyl or methoxybenzylamines could generate
analgesic effects in tail immersion and formalin tests com-
paring to a control group of rats at 6 mg/kg dosage.
ACKNOWLEDGEMENTS
[15]
[16]
[17]
[18]
Celements, J. A.; Nimmo, W.S.; Grant, I.S. Bioavailability, phar-
macokinetics and analgesic activity of ketamine in humans. J.
Pharmaceut. Sci. 1982, 71(5), 539-542.
Pabelick, C.M.; Rehder, K. Stereospecific effects of ketamine
enantiomers on canine tracheal smooth muscle. Br. J. Pharmacol.
1997, 121, 1378-1382.
Takadera, T.; Ishida, A.; Ohyashiki, T. Ketamine-induced apopto-
sis in cultured rat cortical neurons. Toxicol. Appl. Pharmacol. 2006,
210, 100-107.
Boettger, M.K.; Weber, K.; Gajda, M. Spinally applied ketamine or
morphine attenuate peripheral inflammation and hyperalgesia in
acute and chronic phases of experimental arthritis. Brain Behav.
Immun. 2010, 24, 474-485.
This work was a research project sponsored by Islamic
Azad University, Karaj branch, Iran. The authors would like
to express their appreciations to Mojdeh Javadi for assisting
in chemical experiments and Fariba Ansari for conducting
pharmacological tests. The authors also extend their grati-
tude to Dr. Ahmad J. Latibariand, Dr. Natasha Q. Pourdana,
the CamTESOL International editor, for proofreading the
initial drafts of this article.
REFERENCES
[19]
Curtinz, D.; Schmuklerz, S. The Axial Effect in the Rearrangement
with Nitrous Acid of cis- and trans-2-Amino-l-phenylcyclohexanol.
J. Am. Chem. Soc.1955, 77, 1105-1110.
Stevens, C. L. Aminoketones and methods for their production,
U.S. Patent 3, 254, 124, May 31, 1966.
Hamura, H.; Yoshida, M.; Shimizu, K. Antinociceptive effect of
the combination of pentazocine with morphine in the tail-
immersion and scald-pain tests in rats. Jpn. J. Pharmacol. 2000,
83(4), 286-292.
[1]
Domino, E.F.; Chodoff, P.; Corssen, G. Pharmacologic Effects of
CI-581 (A new dissociative anesthetic). Clin. Pharmacol. Ther.
1965, 6, 279-291.
AnirunddaPai, M.; Heining, S. Ketamine: Continuing Education in
Anaesthesia. Crit. Care Pain, 2007, 7(2), 59-63.
Bhutta, A.T. Ketamine: A controversial drug for neonates. Semin.
Perinatol., 2007, 31, 303-308.
Porro, C.A.; Cavazzuti, M.; Giuliani, D. Effect of ketamine anes-
[20]
[21]
[2]
[3]
[4]
thesia on central nociceptive processing in the rat:
A 2-
[22]
[23]
[24]
Padi, S.S.V.; Kulkarni, S.K. Minocycline prevents the development
of neuropathic pain, but not acute pain: Possible anti-inflammatory
and antioxidant mechanisms. Eur. J. Pharmacol. 2008, 601, 79-87.
Dubuisson, D.; Dennis, S.G. The formalin test: a quantitative study
of the analgesic effects of morphine, meperidine, and brain stem
stimulation in rats and cats. Pain, 1977, 4(2), 161-74.
Ahmadi, A.; Khalili, M.; Abbassi, S. Synthesis and Study on Anal-
gesic Effects of 1-[1-[4-methylphenyl][cyclohexyl]-4-piperidinol
and 1-[1-[4-methoxyphenyl][cyclohexyl]]-4-piperidinol as Two
new Phencyclidine Derivatives. Arzneimittelforschung, 2009,
59(4), 202-206.
Molina, N.; Bedran-de-Castro, M.T.; Bedran-de-Castro, J.C. Sex-
related differences in the analgesic response to the rat tail immer-
sion test. Braz. J. Med. Biol. Res. 1994, 27(7), 1669-1672.
Ibba, M.; Schiavi, S.; Abbiati, G. Effects of oral administration of
nortriptyline, imipramine and citalopram on morphine hot-plate and
tail-immersion analgesia in rats. Bull. Chim. Franc. 1987, 126(2),
75-80.
Sewell, R.D.; Spencer, P.S. Antinociceptiveactivitiy of narcotic
agonist and partial agonist analgesics and other agents in the tail-
immersion test in mice and rats. Neuropharmacology, 1976,
15(11), 683-688.
Ahmadi, A.; Khalili, M.; Hajikhani, R.; Naserbakht, M. New mor-
pholine analogues of phencyclidine: Chemical synthesis and pain
perception in rats. Pharmacol. Biochem. Behavior. 2011, 98(2),
227-233.
deoxyglucose study. Neuroscience, 2004, 125, 485-494.
[5]
[6]
Sarton, E.; Teppema, L. J.; Olievier, C. The involvement of the ꢀ-
opiod receptor in ketamine-induced respiratory depression and an-
tinociception. Anesth. Analg. 2001, 93, 1495-1500.
Stevens, C.L.; Thuillier, A.; Taylor, K.G. Aminoketones rear-
rangements. Synthesis of 2-methylamino-2-substituted phenylcy-
clohexanones. J. Org. Chem. 1966, 31, 2601-2607.
Woolf, T.; Trevor, A.; Baillie, T. Synthesis of (Z)- and (E)-6-
hydroxyketamine. J. Org. Chem. 1984, 49, 3305-3310.
Yang, D.J.; Davisson, N. Aminotetralone analogues of ketamine:
Synthesis and evaluation of hypnotic and locomotor properties in
mices. J. Med. Chem. 1985, 28, 1361-1365.
Shiue, C.Y.; Vallabhahosula, S.; Wolf, A.P. Carbon-11 labeled
ketamine-synthesis, distribution in mice and pet studies in baboons.
Nuclear Med. Biol. 1997, 24, 145-150.
Yokoyama, R.; Matsumoto, S.; Nomura S. Enantioselective con-
struction of nitrogen-substituted quaternary carbon centers adjacent
to the carbonyl group in the cyclohexane ring: first asymmetric
synthesis of anesthetic (S)-ketamine with high selectivity. Tetrahe-
dron, 2009, 65, 5181-5191.
Mathisen, L.C.; Skjelbred, P.; Skoglund, L.A. Effect of ketamine,
an NMDA receptor inhibitor, in acute and chronic orofacial pain.
Pain, 1995, 61, 215-220.
[7]
[8]
[25]
[26]
[9]
[10]
[27]
[28]
[11]
[12]
Sadove, M.S.; Shulman, M.; Hatano, S. Analgesic effects of keta-
mine administered in subdissociative doses. AnesthAnalg, 1971, 50,
452-457.
Received: April 08, 2011
Revised: July 31, 2011
Accepted: August 06, 2011