Synthesis and Comparative Bioefficacy of N-(1-Phenethyl-4-Piperidinyl)Propionanilide (Fentanyl) and Its 1-Substituted Analogs in Swiss Albino Mice [Med. Chem. Res., 2013, 22, 8, 3888–3896; 10.1007@s00044-012-0390-6]
Synthesis and Comparative Bioefficacy of N-(1-Phenethyl-4-Piperidinyl)Propionanilide (Fentanyl) and Its 1-Substituted Analogs in Swiss Albino Mice [Med. Chem. Res., 2013, 22, 8, 3888–3896; 10.1007@s00044-012-0390-6]
(1-phenethyl-4-piperidinyl)propionanilide
(fentanyl) and its 1-substituted analogs in
Swiss albino mice
ISSN 1054-2523
Volume 22
Number 8
1 23
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Med Chem Res (2013) 22:38883896 MEDICINAL
DOI 10.1007/s00044-012-0390-6
CHEMISTRY
RESEARCH
ORIGINAL RESEARCH
Received: 24 April 2012 / Accepted: 4 December 2012 / Published online: 15 December 2012
Springer Science+Business Media New York 2012
Abstract Fentanyl [N-(1-phenethyl-4-piperidinyl)propi- The lowest ED50 (23.7) and the highest potency ratio (1.18)
onanilide] is a popular narcotic analgesic agent that is was observed in the case of 2. However, the maximum
clinically used worldwide. However, fentanyl and its sev- therapeutic index was afforded by 4. The study indicates the
eral analogs have caused abuse and fatalities in humans due promising role of some new opioid analgesics.
to overdosing and narrow therapeutic index. The present
study reports the synthesis and comparative bioefficacy of Keywords Fentanyl Opioids 1-Substituted analogs
fentanyl and its four analogs, viz., N-(1-propyl-4-piperidinyl) Synthesis Bioefficacy Mice
propionanilide (1), N-(1-(2-phenoxyethyl)-4-piperidinyl)pro-
pionanilide (2), N-(1-(3-phenoxypropyl)-4-piperidinyl)propi-
onanilide (3) and N-(1-(2-cyanoethyl)-4-piperidinyl)propionanilide Introduction
(4), where the phenethyl chain of fentanyl was replaced by
different functional groups, viz., alkyl, ethereal, and nitrile The treatment of mild to moderate pain can typically be
moieties. The median lethal dose (LD50) of the compounds accomplished with non-narcotic analgesics. These drugs
was determined by three different routes and all the analogs are relatively inexpensive, but are ineffective for the
were found to be safer than fentanyl. Observational assess- treatment of severe pain, for which more potent drugs, viz.,
ment on spontaneous activities of the central nervous sys- narcotic analgesics are used. Fentanyl is a popular synthetic
tem, peripheral nervous system, and autonomic nervous narcotic analgesic that is classified as schedule II-con-
system revealed that all the analogs were similar to fentanyl. trolled drug and is clinically used worldwide. It has rapid
Further, the neurotoxic effects of all the analogs were onset and short duration of action, good overall safety
reversed by naloxone hydrochloride (opioid antagonist), margin, and is several times more potent than morphine
confirming that their effects were mediated through opioid (Mather, 1983; Van Nimmen et al., 2004; Micovic et al.,
receptors. Antinociceptive activity was displayed by all the 2000). Fentanyl is a synthetic l-opioid receptor agonist,
compounds and their median effective dose (ED50) and widely used for surgical analgesia and sedation (Hug and
analgesic potency ratio were more or less similar to fentanyl. Murphy, 1981). Most of the effects like analgesia, eupho-
ria, and respiratory depression displayed by fentanyl are
typical of other opioids. Opioid receptors are coupled with
P. K. Gupta K. Ganesan G-protein receptor and function as both positive and neg-
Division of Synthetic Chemistry, Defence Research and ative regulators, and are principally found in the central
Development Establishment, Jhansi Road, Gwalior 474 002,
nervous system (CNS) and the gastrointestinal tract. The
Madhya Pradesh, India
receptors mediate both the beneficial effects and the side
S. K. Yadav Y. D. Bhutia P. Singh P. Rao effects of opioids. The analgesic (painkiller) effects of
N. L. Gujar R. Bhattacharya (&) opioids are due to decreased perception of pain and
Division of Pharmacology and Toxicology, Defence Research
impaired reaction to pain, as well as increased pain toler-
and Development Establishment, Jhansi Road, Gwalior 474 002,
Madhya Pradesh, India ance. In addition to analgesia, alterations in mood,
e-mail: [email protected] euphoria and dysphoria, and drowsiness commonly occur.
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Med Chem Res (2013) 22:38883896 3889
It depresses the respiratory centers and cough reflex, and antagonist) to ascertain that their effects were mediated
constricts the pupils (Fine, 2004; McNicol et al., 2008). through opioid receptors. Antinociceptive activity and
Although, fentanyl is very popular, its several analogs have toxicity of all the compounds were measured by median
caused abuse and fatalities in humans, which led to syn- effective dose (ED50) and median lethal dose (LD50),
thesis of some more potent and safer analogs (Higashikawa respectively. The study reveals that replacing the phenyl
and Suzuki, 2008). group of phenethyl tail of fentanyl with different functional
Over the last four decades, structureactivity relation- groups results in decreased toxicity of the molecules
ship and molecular modeling studies of fentanyl analogs without sacrificing their potency. Thereby, enhanced ther-
provided considerable insight into the key structural fea- apeutic index could be achieved.
tures and pharmacophore elements required for high-
affinity binding to the l-receptor (Helsley et al., 1969;
Van Bever et al., 1974). From these studies, it was pro- Materials and methods
posed that a number of structural elements were required
for the analgesic activity of fentanyl class of compounds, Synthesis of fentanyl and its analogs
and variations in these pharmacological parameters led to
the synthesis of novel potent analogs of fentanyl All the chemicals of highest purity, including dimethyl sulf-
(Vuckovic et al., 1998). The strong potency of fentanyl in oxide (DMSO), naloxone hydrochloride, and formalin were
relation to that of morphine is largely due to its high purchased from Sigma-Aldrich Inc. (St. Louis, USA). Fentanyl
lipophilicity that facilitates its easy penetration into the [N-(1-phenethyl-4-piperidinyl)propionanilide], N-(1-propyl-4-
CNS (Ivanovic et al., 1995). The presence of an aromatic piperidinyl)propionanilide (1), N-(1-(2-phenoxyethyl)-4-pipe-
ring attached to the piperidine ring nitrogen was supposed ridinyl)propionanilide (2), N-(1-(3-phenoxypropyl)-4-piperid-
to be responsible for the favorable lipophilic interaction inyl)propionanilide (3), and N-(1-(2-cyanoethyl)-4-piperidinyl)
of the molecules at the receptor site. Its replacement with propionanilide (4) were synthesized in the Synthetic Chemistry
groups with differing polarities may produce clinically Division of Defence Research and Development Establishment
more useful compounds with better pharmacological (DRDE), Gwalior. The test compounds were prepared as per the
profile. In the present study, different fentanyl analogs, following scheme by the modification of the classical method
where the phenyl group of the phenethyl chain of fentanyl reported elsewhere (Janssen, 1965).
was replaced with groups of differing polarities, viz., The conversion of commercially available N-benzyl-4-
alkyl, ethereal and nitrile moieties, were synthesized and piperidone (NBP; 5) to 4-anilino-N-benzylpiperidine
evaluated for their bioefficacy. (ANBP; 6) was carried out in two steps, first involving the
At normal environmental temperature, a single intra- reaction of 5 with aniline to give corresponding imine, which
peritoneal (ip) administration of fentanyl to unrestrained was then reduced with sodium borohydride to give 6. In the
rats has been shown to evoke analgesia and behavioral present method, this conversion was effected in single step
effects such as catalepsy, hyperexcitability, loss of righting involving the reaction of 5 and aniline in the presence of zinc
reflex, and corneal reflex, accompanied by changes in body and acetic acid to give the desired product 6. Transformation
temperature (Vuckovic et al., 1998; Ivanovic et al., 1995). of 6 to N-(4-piperidinyl)propionanilide (PP; 8) was carried
In the present study, observational assessment on the basis out as per the reported method involving acylation with
of behavioral parameters representing the activities of propionyl chloride to give N-(1-benzyl-4-piperidinyl)pro-
CNS, peripheral nervous system (PNS), and autonomic pionanilide (BPP; 7) followed by its debenzylation in pres-
nervous system (ANS) was evaluated after administration ence of 10 % palladiumcharcoal. Compound 8 acted as a
of the compounds by intravenous (iv), ip and per oral (po) common precursor and once this key intermediate was in
routes in mice. The neurotoxic effects of all the compounds hand, (N-alkylpiperidin-4-yl)propionanilides, all the com-
were challenged by naloxone hydrochloride (opioid pounds were prepared by its reaction with different alkyl
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Med Chem Res (2013) 22:38883896 3891
KBr): 3050, 2953, 2853, 2527, 1652, 1598, 1494, 1452, rice husk as the bedding materials with free access to food
1399, 1268, 1149, 762, 708 cm-1. 1H NMR [400 MHz, (Ashirwad Brand, Chandigarh, India) and water. Before
CDCl3, d(ppm)]: 0.84 (t, 3H), 1.01 (t, 3H), 1.371.45 (m, experiment, animals were randomized and acclimatized for
4H), 1.75 (bd, 2H), 1.91 (q, 2H), 2.04 (bt, 2H), 2.22 (t, 2H), 7 days at 12-h lightdark cycle. The care and maintenance
2.90 (bd, 2H), 4.66 (m, 1H), 7.06 (d, 29 ArH), 7.347.38 of the animals were as per the approved guidelines of the
(m, 39 ArH). EI-MS (m/z): 276 [M ? 2]?, 275 Committee for the Purpose of Control and Supervision of
[M ? 1]?, 274 [M]?, 245, 217, 202, 189, 172, 158, 146, Experiments on Animals (CPCSEA), India. Animals were
132, 130, 126, 124, 118, 98, 96, 84, 82, 77, 70, 57, 55, 44, fasted overnight and allowed access to food and water 2-h
42. post-exposure. Animal experiments were carried out with
the approval of Institutional Animal Ethical Committee.
N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2)
Determination of LD50
Molecular formula: C22H28N2O2, crystalline solid, yield:
78 %, mp 9394 C. IR (m, KBr): 3060, 2953, 2845, 2797, Acute LD50 (iv, ip, and po) of the compounds was deter-
1649, 1598, 1491, 1465, 1450, 1373, 1258, 1249, 1153, mined by Dixons up and down method using 4-6 animals
1052, 1038, 757, 706 cm-1. 1H NMR [400 MHz, CDCl3, for each value (Dixon, 1965). All the compounds were
d(ppm)]: 1.011 (t, 3H), 1.42 (dq, 2H), 1.76 (bd, 2H), 1.92 dissolved in DMSO and administered in a volume \10 ml/
(q, 2H), 2.25 (bt, 2H), 2.74 (t, 2H), 3.00 (bd, 2H), 4.02 (t, kg body weight. To determine the iv LD50, the compounds
2H), 4.68 (m, 1H), 6.84 (d, 29 ArH), 6.91 (t, 19 ArH), were administered through tail vein using a 27-gauge
7.07 (dd, 29 ArH), 7.227.26 (dd, 29 ArH), 7.35-7.40 needle, and for the po LD50, a 16-gauge oral feeding
(m, 39 ArH). EI-MS (m/z): 295, 258, 245 (100), 202, 189, cannula (HSE-Harvard, Germany) was used. Although the
176, 158, 146, 132, 118, 108, 96, 93, 77, 65, 57. animals were observed for 14 days, the mortality invari-
ably occurred within the first 24 h. All the dead animals
N-(1-(3-phenoxypropyl)-4-piperidinyl)propionanilide (3) were autopsied to see any visceral changes.
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divided into six groups of 27 animals each as follows: the therapeutic index was calculated as the ratio of LD50 of
(i) vehicle control (DMSO), (ii) Fentanyl, (iii) 1, (iv) 2, the compounds and their corresponding ED50.
(v) 3, and (vi) 4. Three animals from each group received
0.25, 0.50, 0.75 LD50 each of the compounds by iv, ip, and Measurement of analgesic activity
po routes. Immediately after administration, the animals
Analgesic activity of all the compounds was measured at
were closely observed for 2 h by a blind observer for
their ED50, following the method discussed elsewhere
various behavioral effects on CNS, PNS, and ANS as
(Hunskar and Hole, 1987; Vogel, 2002; Ellis et al., 2008).
enumerated below (Table 1).
Determination of opioid antagonist activity Table 3 Observational assessments after intravenous administration
of fentanyl and its analogs in mice
In order to ascertain that the effects of all the compounds Compounds Dose CNS PNS ANS
were mediated through opioid receptors, naloxone hydro- After Reflexes
chloride (opioid antagonist) was dissolved in normal saline manipulations
and subcutaneously (sc) injected (5.0 mg/kg) in mice
Control 0 0 0 0
10 min before administration of fentanyl and its analogs
(0.50 LD50; ip) (Leavitt, 2009; Matosiuk et al., 2002). Fentanyl Low ?? ?? ?? ?
Three animals were used for each compound. Immediately Medium ??? ??? ??? ?
after administration, the animals were closely observed for High ???? ???? ??? ?
its neurotoxic effects as mentioned in Table 1 and com- 1 Low ?? ?? ?? ?
pared with the effects observed in animals receiving the Medium ??? ?? ??? ?
compounds (0.50 LD50; ip) without naloxone. High ??? ??? ??? ??
2 Low ??? ?? ?? ?
Medium ??? ??? ??? ?
Determination of ED50, potency ratio, and therapeutic High ???? ??? ??? ?
index 3 Low ?? ?? ?? ?
Medium ?? ?? ?? ?
Analgesic ED50 of fentanyl and its analogs was determined High ??? ??? ??? ??
by formalin-induced hind paw licking method (Hunskar 4 Low ?? ?? ?? ?
and Hole, 1987). Each compound was assessed using four Medium ?? ?? ?? ??
different doses, and four animals for each dose. All the High ??? ??? ??? ??
compounds were dissolved in DMSO and administered ip
30 min before administration of formalin (2.5 %, 20 ll) Mice were intravenously administered 0.25 (Low), 0.50 (Medium),
and 0.75 (High) LD50 of fentanyl and its four analogs, viz., 14 The
injected subplantarly in one hind paw. The duration of paw control animals received DMSO. Immediately after treatment, the
licking as index of nociception was monitored at 05 min animals were closely observed for 2 h by a blind observer for its
(early phase) and 1530 min (late phase) intervals. The effects on CNS, PNS (effects after manipulation and effects on
ED50 was calculated by the method of Litchfield and reflexes), and ANS activities. The scorings were given as 0 (no
observational change), ? (little activity), ?? (moderate flexibility),
Wilcoxon (1949). The potency ratio was determined as the ??? (strong response), and ???? (exaggerated response). Each
ratio of ED50 of fentanyl and the ED50 of each analog and treatment included three animals
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Med Chem Res (2013) 22:38883896 3893
This method includes useful models, particularly for the Results and discussion
screening of novel compounds, since it encompasses
inflammatory, neurogenic, and central mechanisms of Toxicity of the compounds
nociception. Mice were divided into six groups of six
animals each and received various treatments by ip route as Table 2 refers to the LD50 of fentanyl and its analogs by
follows: (i) vehicle control (DMSO), (ii) Fentanyl different routes of administration in mice. On the basis of
(28.0 lg/kg), (iii) 1 (26.7 lg/kg), (iv) 2 (23.7 lg/kg), (v) 3 iv and ip LD50, toxicity of the compounds were in the
(31.8 lg/kg), and (vi) 4 (33.3 lg/kg). Thirty minutes after following order: Fentanyl [ 3 [ 2 [ 1 [ 4, while the
the administration of different compounds, formalin same for po route was: Fentanyl [ 3 [ 1 [ 2 [ 4. The
(2.5 %, 20 ll) was injected subplantarly in one hind paw. LD50 of fentanyl was 6.9, 17.5, and 27.8 mg/kg for iv, ip,
The duration of paw licking as an index of nociception was and po routes, respectively, while the same for 4 was 69.8,
monitored at 05 min (early phase) and 1530 min (late 285.8, and 717.9 mg/kg body weight, respectively. By all
phase) intervals. the routes of administration, fentanyl was found to be the
most toxic and 4 the least toxic. As per the material safety
data sheet, the LD50 of fentanyl citrate in mice is 2.9, 7.6,
Statistics and 368 mg/kg for iv, ip, and po routes, respectively
(MSDS, 2009). Elsewhere, the LD50 values are reported to
Results of analgesic activity were expressed as mean SE be 11.2 and 62 mg/kg for iv and sc routes, respectively
(n = 6). The statistical analysis was performed by Stu- (Gardocki and Yelnosky, 1964) and for po route it is
dents t test by means of SigmaStat software (SSP Inc., 62 mg/kg (Higashikawa and Suzuki, 2008). This kind of
USA). Statistical significance was drawn at p \ 0.01. large variation in LD50 values can be attributed to different
Table 4 Observational assessments after intraperitoneal administra- Table 5 Observational assessments after oral administration of fen-
tion of fentanyl and its analogs in mice tanyl and its analogs in mice
Compounds Dose CNS PNS ANS Compounds Dose CNS PNS ANS
After Reflexes After Reflexes
manipulations manipulations
Control 0 0 0 0 Control 0 0 0 0
Fentanyl Low ?? ??? ? ? Fentanyl Low ?? ?? ?? ?
Medium ??? ???? ?? ? Medium ??? ??? ?? ?
High ???? ???? ??? ? High ???? ??? ??? ?
1 Low ?? ?? ? ? 1 Low ?? ?? ? ?
Medium ??? ?? ?? ?? Medium ?? ?? ?? ?
High ??? ??? ??? ?? High ??? ??? ?? ?
2 Low ?? ?? ?? ? 2 Low ? ? ? ?
Medium ??? ?? ??? ? Medium ??? ?? ?? ?
High ???? ??? ??? ? High ???? ??? ??? ?
3 Low ?? ?? ? ? 3 Low ?? ?? ? ?
Medium ??? ?? ?? ?? Medium ?? ?? ?? ?
High ??? ??? ?? ?? High ??? ??? ??? ?
4 Low ?? ?? ?? ? 4 Low ?? ? ? ?
Medium ??? ?? ?? ? Medium ?? ?? ? ??
High ??? ?? ?? ? High ??? ??? ?? ??
Mice were intraperitoneally administered 0.25 (Low), 0.50 (Medium), Mice were orally administered 0.25 (Low), 0.50 (Medium), and 0.75
and 0.75 (High) LD50 of fentanyl and its four analogs, viz., 14 The (High) LD50 of fentanyl and its four analogs, viz., 14. The control
control animals received DMSO. Immediately after treatment, the animals received DMSO. Immediately after treatment, the animals
animals were closely observed for 2 h by a blind observer for its were closely observed for 2 h by a blind observer for its effects on
effects on CNS, PNS (effects after manipulation and effects on CNS, PNS (effects after manipulation and effects on reflexes), and
reflexes), and ANS activities. The scorings were given as 0 (no ANS activities. The scorings were given as 0 (no observational
observational change), ? (little activity), ?? (moderate flexibility), change), ? (little activity), ?? (moderate flexibility), ??? (strong
??? (strong response), and ???? (exaggerated response). Each response), and ???? (exaggerated response). Each treatment
treatment included three animals included three animals
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Table 6 ED50, potency ratio and therapeutic index of fentanyl and its analogs in mice
Compounds ED50 (lg/kg) Potency ratio Therapeutic index
animal species and salts of fentanyl used. Mice succumbing interneurons (McGinty and Friedman, 1988). Also, in our
to lethal doses of the compounds administered through study, there were reduced ANS symptoms like defecation
different routes were autopsied immediately after death. and micturation, typical of opioid analgesics. In the present
Profuse intestinal hemorrhage was evident in most of the study, we evaluated the compounds through parenteral and
corpses, which perhaps led to hypovolemic shock and po routes of administration, which are the preferred routes
resultant death. This was very similar to the observations of opioids for pain management (Gardocki and Yelnosky,
made previously with methyl-substituted and para-substi- 1964; Vuckovic et al., 2011; Hallenbeck, 2003). In the
tuted fentanyl (Higashikawa and Suzuki, 2008). present study, to ascertain the efficacy of the compounds,
we evaluated them by three different routes, viz., iv, ip, and
Observational assessment po. Also, most of the motor coordination and behavioral
tests for initial screening remained same as reported earlier
Observational assessment on spontaneous CNS, PNS, and (Gardocki and Yelnosky, 1964).
ANS activities of the animals following administration of
various compounds by iv, ip, and po routes are summarized
in Tables 3, 4, and 5, respectively. The activities produced Test for opioid antagonist activity
by the compounds administered through iv and ip routes
were more intense as compared to po route. Also, the CNS Short acting naloxone and long acting naltrexone are the
and PNS activities were more noticeable as compared to two opioid antagonists that have been most extensively
ANS. In general, no appreciable doseresponse effects
were observed, but effects in medium and high dose were 100
certainly more severe as compared to low dose. Effects on First Phase
Time spent in paw licking (sec)
CNS, PNS, and ANS activities were more in fentanyl and 2 Second Phase
80
as compared to others. The results indicate that all the
analogs exhibited effects almost similar to the parent
compound, fentanyl. The effects were much prominent 60
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Med Chem Res (2013) 22:38883896 3895
used to treat opioid addiction (Leavitt, 2009). In the present excitatory amino acids (Correa and Calixto, 1993; Damas
study, naloxone quickly reversed the observed neurotoxic and Liegeois, 1999). This late phase is inhibited by NSA-
effects of all the compounds, confirming that their effects IDs and opioid analgesics. In our study, fentanyl and
were mediated through opioid receptor (Micovic et al., analogs were more effective in the later phase rather than
2000; Leavitt, 2009; Matosiuk et al., 2002). in the first phase, testifying the fact that these compounds
could be inhibitors of the pain mediators during the late
ED50, potency ratio and therapeutic index phase.
of the compounds
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Hunskar S, Hole K (1987) The formalin test in mice: dissociation Micovic IV, Ivanovic MD, Vuckovic SM, Prostran MS, Dosen-
between inflammatory and non-inflammatory pain. Pain 30: Micovic L, Kiricojevic VD (2000) The synthesis and preliminary
103114 pharmacological evaluation of 4-methyl fentanyl. Biorg Med
Irwin S (1964) Drug screening and evaluation of new compounds in Chem Letts 10:20112014
animals. In: Nodin JH, Siegler PE (eds) Animal and clinical Perlikowska R, Fichna J, Claude de-Rego J, Gach K, Janecka A
techniques in drug evaluation. Year Book Medical Publishers, (2011) Kinetic studies of novel inhibitors of endomorphine
Chicago, pp 3654 degrading enzymes. Med Chem Res. doi:10.1007/s00044-
Irwin S (1968) Comprehensive observational assessment: Ia. A 011-9666-5
systematic, quantitative procedure for assessing the behavioural Qi H, Li W, Qiu Y, Cui Y, Ma J, Gao X, Zeng Y, Yang J, Tang Y,
and physiologic state of the mouse. Psychopharmacologia (Berl) Wang X, Sheng W, Xie Q, Liu J, Qiu Z, Chen H (2011)
13:222257 Synthesis and evaluation of k-opioid receptor agonistic activity
Ivanovic MD, Vuckovic S, Ristovic Z, Micovic IV, Beleslin DB and antinociceptive effect of novel morphine analogues, 7a-
(1995) Behavioral effects of fentanyl in rats. Iugav Physiol phenyl-6a, 14a-endo-etheno-tetrahydrothebaine with substituted
Pharmacol Acta 31:195199 o-, m- and p-amino group. Med Chem Res 20:13641370. doi:
Janssen PAJ (1965) 1-Aralkyl-4-(N-aryl carbonylamino)piperidines 10.1007/s00044-010-9471-6
and related compounds. US Patent 3, 164 600 Shibata M, Ohkubo T, Takashi H, Inoki R (1989) Modified formalin
Johnson M (2009) MSDS on fentanyl citrate. Macfarlan Smith test. Pain 38:345352
Limited, Edinburgh Van Bever WFM, Niemegeers CJE, Janssen PAJ (1974) Synthetic
Leavitt SB (2009) Opioid antagonists, naloxone & naltrexene-Aids analgesics. Synthesis and pharmacology of the diastereoisomers
for pain management. An overview of clinical evidence. Pain of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropan-
Treatment Topics, Glenview, IL, 60025. http://Pain-Topics.Org, amide and N-[3- methyl-1-(1-methyl-2-phenylethyl)-4-piperi-
116 dyl]-N-phenylpropanamide. J Med Chem 17:10471051
Litchfield JT Jr, Wilcoxon F (1949) A simplified method of evaluating Van Nimmen NFJ, Poels KLC, Veulemans HAF (2004) Highly sensitive
dose-effect experiments. J Pharm Exp Ther 96:99113 gas chromatographic-mass spectrometric screening method for the
Mather LE (1983) Clinical pharmacokinetics of fentanyl and its determination of pictogram levels of fentanyl, sufentanil and
newer derivatives. Clin Pharmacokinet 8:422446 alfentanil and their major metabolites in urine of opioid exposed
Matosiuk D, Fidecka S, Antkiewicz-Michaluk L, Lipkowski J, Dybala I, workers. J Chromat B 804:375387
Koziol AE (2002) Synthesis and pharmacological activity of new Vogel HG (2002) Psychotropic and neurotropic activity. In: Drug
carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Part 2. Syn- discovery and evaluation. Pharmacological assays. Springer, Berlin
thesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2, Vuckovic S, Ivanovic M, Prostran M, Todorovic Z, Ristovic Z, Micovic
3-dihydroimidazo[1,2-a][1,3,5]triazines. Eur J Med Chem 37: I, Beleslin D (1998) Higher environmental temperature potentiates
761772 cataleptic effect of fentanyl. Jpn J Pharmacol 78:523527
McGinty J, Friedman D (1988) Opioids in the hippocampus. Natl Inst Vuckovic S, Prostran M, Ivanovic M, Dosen-Micovic L, Vujovic KS,
Drug Abuse Res Monogr Ser 82:1145 Vucetic C, Kadija M, Micovic Z (2011) Pharmacological
McNicol E, Boyce D, Schumann R, Carr D (2008) Mu-opioid evaluation of 3-carbomethoxy fentanyl in mice. Pharmaceuticals
antagonists for opioid-induced bowel dysfunction. Cochrane 4:233243
Database Syst Rev. CD006332. PMID 18425947
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