Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2- yl)ethyl)azepane-4-yl)propionamide in the mouse tail-flick and hot-plate tests

Article abstract of DOI:10.1016/j.bmcl.2013.11.069

The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2- yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, α₂-adrenergic, and I₂ imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ET_A receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists + 1c; clonidine + 1c; or antagonists + clonidine + 1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α₂-adrenoceptor antagonist), idazoxan (α₂-adrenoceptor/I₂-imidazoline antagonist), BU224 (I₂-imidazoline antagonist) or BQ123 (endothelin ET_A receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED₅₀ values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The α₂-adrenergic, I₂-imidazoline and endothelin ET _A receptors are not involved in 1c antinociception.

Full text of DOI:10.1016/j.bmcl.2013.11.069

Bioorganic & Medicinal Chemistry Letters 24 (2014) 644–648
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antinociceptive properties
of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)
propionamide in the mouse tail-flick and hot-plate tests
a
a
b
Shridhar V. Andurkar a, , Madhu Shaw J. Reniguntala , Anil Gulati , Jack DeRuiter
⇑
a Department of Pharmaceutical Sciences, Midwestern University, Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, USA
b Department of Pharmacal Sciences, Auburn University Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propi-
onamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception
Received 23 October 2013
Revised 19 November 2013
Accepted 25 November 2013
Available online 4 December 2013
and the involvement of opioid,
a2-adrenergic, and I2 imidazoline receptors in 1c antinociception were
studied. Also examined was the effect of an endothelin ETA receptor antagonist on 1c antinociception.
Synthesis of 1c was accomplished in two steps using modifications of previously reported methods.
Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated
with 1c; antagonists + 1c; clonidine + 1c; or antagonists + clonidine + 1c. Mice were pretreated with nal-
Keywords:
Antinociception
Opioid receptor
Fentanyl
Clonidine
Adrenergic receptor
Imidazoline receptor
oxone (opioid antagonist), yohimbine (a2-adrenoceptor antagonist), idazoxan (a2-adrenoceptor/I2-imi-
dazoline antagonist), BU224 (I2-imidazoline antagonist) or BQ123 (endothelin ETA receptor antagonist)
to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antin-
ociceptive latencies; ED50 values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot
plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither cloni-
dine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent
than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The
I2-imidazoline and endothelin ETA receptors are not involved in 1c antinociception.
a2-adrenergic,
Ó 2013 Elsevier Ltd. All rights reserved.
The synthesis and antinociceptive activity of a series of per-
hydroazepine (PHA) analogs (1a, Fig. 1) was reported previously.1
The PHAs were designed as ring expanded analogs of the 4-anili-
dopiperidine analgesics, of which fentanyl (Fig. 1) is the proto-
type.2 Studies indicated that the PHAs possessed significant
antinociceptive properties. The most potent compound in this
study, 1a, exhibited antinociceptive potency that was comparable
to that of morphine and about 100-fold lower than the potency
of fentanyl (Table 1) in the mouse tail-flick test.1 The antinocicep-
tive actions of 1a were blocked by the opioid antagonist naloxone,
confirming its actions via the opioid receptors.1 In a subsequent
study, an improved synthetic method of the PHAs was employed
to synthesize additional analogs and the synthesis and antinoci-
ceptive activity of 1b was reported.3 Compound 1b was designed
by introducing a hydroxyl group in the N-phenethyl side chain of
1a (Fig. 1). This structural modification resulted in a 10-fold in-
crease in the antinociceptive potency of 1b in the mouse tail flick
test compared to 1a (Table 1).3 In view of the possibility of further
enhancing the antinociceptive potency of the PHAs by modifying
the N-substituent, and expanding the scope of the structure–activ-
ity relationship of the PHAs, we synthesized the thiophen-2-yl ana-
log 1c (Fig. 1) and tested its antinociceptive activity in the mouse
tail-flick and hot-plate tests. A similar modification to the structure
of fentanyl resulted in the synthesis of NIH 10505 (Fig. 1) which
proved to be almost as active as fentanyl in the mouse tail-flick as-
say (Table 1).4 The involvement of opioid receptors in mediating 1c
antinociception was studied using opioid antagonist naloxone.
The
opioid antinociception. Studies have shown a physical and func-
tional interaction between opioid and
2-adrenergic receptors5,6
and that the 2-adrenergic receptors play a variable role in opioid
antinociception.5,7 It was demonstrated that meperidine, remifen-
tanil and tramadol but not sufentanil bind to 2-adrenergic recep-
tors.8 In another study, morphine, but not fentanyl, was shown to
interact with
2-adrenergic receptors.9 Morphine and tramadol
antinociception is blocked by the
a2-adrenergic and the I2-imidazoline receptors influence
a
a
a
a
a
2-adrenergic receptor antagonist
yohimbine.10–13 Another study reported that the antinociceptive ef-
fects of tramadol or buprenorphine, but not of fentanyl or mor-
phine, were significantly enhanced by pretreatment with
yohimbine or in
own studies have shown that tramadol antinociception is not
a
2A-adrenergic receptor knockout mice.14 Our
⇑
Corresponding author. Tel.: +1 630 515 6399; fax: +1 630 515 6958.
E-mail address: sandur@midwestern.edu (S.V. Andurkar).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.11.069

S. V. Andurkar et al. / Bioorg. Med. Chem. Lett. 24 (2014) 644–648
645
O
N
O
N
O
N
O
H
O
H
H
H
H
N
N
N
N
N
N
N
OH
S
S
1b
1c
1a
Fentanyl
NIH 10505
Figure 1. Chemical structures of fentanyl, NIH 10505, and compounds 1a, 1b and 1c.
properties of 1c in the mouse tail-flick and hot-plate tests; (3)
determine the involvement of opioid, 2-adrenergic, and I2 imidaz-
Table 1
a
Antinociceptive activities of selected compounds
oline receptors in 1c antinociception; (4) study the effect of cloni-
dine on 1c antinociception; (5) determine the involvement of
Compound
ED50 mg/kg, sc (95% CL)a
Fentanyl
NIH 10505
1a
1b
1c
0.015 (0.013–0.018)b
0.03 (0.02–0.05)c
1.5 (0.9–2.6)d
opioid,
a2-adrenergic and I2-imidazoline receptors in clonidine-
mediated potentiation of 1c antinociception; and (6) determine
the effect of endothelin ETA receptor antagonists on 1c
antinociception.
0.13 (0.071–0.25)b
0.15 (0.12–0.19)
2.2 (1.5–3.2)b
Morphine
All synthetic and pharmacologic methods employed in this
study are described in detail in the Supplementary data. The syn-
thesis of 1c is outlined in Scheme 1. The 4-anilino intermediate 2
was obtained from previously reported methods3 and was allowed
to react with mesylate 334 using modifications as previously
described,34 to obtain the N-alkylated intermediate 4. Treatment
of 4 with propionic anhydride afforded 1c.3 All intermediates and
final products were obtained in satisfactory yields after purifica-
tion using standard methods. Intermediates and final products
were characterized with IR, 1H, 13C NMR, mass spectrometry and
gave spectra that corroborated with the expected structures, as ci-
ted in the Supplementary data. The free base of 1c was converted
to the citrate salt and gave elemental analysis consistent with
the monocitrate salt. All pharmacological studies were conducted
on the citrate salt of 1c.
a
ED50 in mouse tail-flick assay following subcutaneous administration.
b
c
Data from Ref. 3.
Data from Ref. 4.
Data from Ref. 1.
d
blocked by yohimbine or idazoxan (a2-adrenergic/I2-imidazoline
receptor antagonist).15 Fentanyl antinociception was blocked by
idazoxan in a model of inflammation.16 The imidazoline I2 receptor
also is emerging as an important target for antinociceptives.17 Stud-
ies have revealed a functional interaction between opioids and imi-
dazoline I2 ligands. Imidazoline I2 receptor ligands enhance
tramadol antinociception18 and modulate morphine antinocicep-
tion.19 An additive antinociceptive effect was observed when mor-
phine was co-administered with ligands selective for the
imidazoline I2 site.20 Given the influence of the two receptors on
opioid antinociception, we wanted to investigate the possible
We first established
a
dose-antinociceptive response
relationship for 1c in the mouse tail-flick and hot-plate tests. A
dose-dependent increase in tail-flick and hot-plate latencies was
observed (Fig. 2). Peak effect was observed 30 min after
administration of 1c; typical baseline latencies following vehicle
administration were about 2 s and 11 s for the tail-flick and hot-
plate tests, respectively. Significant antinociception was noted up
to 4 h after administration of the highest dose of 1c in the tail-flick
test (Fig. 2). On the other hand, in the hot-plate test, significant
antinociceptive effect compared to vehicle lasted only for about
90 min (Fig. 2) after administration of 1c. Using the time of peak
effect obtained from the dose–response experiments, tail-flick
and hot-plate latencies were measured 30 min after administration
of five different doses of 1c and ED50 values were calculated using
the method of Litchfield and Wilcoxon.35 The ED50 values for 1c
were 0.15 mg/kg and 0.16 mg/kg in the tail-flick and hot-plate
tests, respectively. The prototype PHA analog 1a has an ED50 of
1.5 mg/kg (Table 1) in the mouse tail-flick test.1 Thus, replacement
of the phenyl ring in 1a with the thiophene ring in 1c (Fig. 1) re-
sulted in a significant 10-fold increase in the antinociceptive effect
of 1c. The thiophene ring is more polar and electron rich than the
phenyl ring and this could contribute to altered in vivo distribution
or pharmacodynamic interactions of 1c, resulting in enhanced
antinociception compared to 1a.36 Interestingly, the corresponding
modification of fentanyl to NIH 10505 (Fig. 1, Table 1) produced a
marginal decrease in antinociceptive effect. The antinociceptive ef-
fect of 1c was blocked by naloxone (Fig. 3) in the tail-flick and the
hot-plate tests, indicating that opioid receptors are involved in 1c
involvement of the
antinociception produced by the PHA analog 1c. Involvement of
these receptors was studied using yohimbine ( 2-adrenergic recep-
tor antagonist), idazoxan ( 2-adrenergic/I2-imidazoline antagonist)
and BU224 (I2-imidazoline receptor antagonist).21,22
Clonidine and other
a2-adrenergic/I2-imidazoline receptors in the
a
a
a2-adrenergic agonists are often used as an
adjuvants to opioids.23,24 Clonidine potentiates the antinociceptive
effects of morphine,21,25 and other opioids including meperidine,
fentanyl, sufentanil and tramadol.15,21,26–30 We have demonstrated
that idazoxan or yohimbine blocks clonidine potentiation of mor-
phine, oxycodone or tramadol antinociception implying the role
of I2-imidazoline/a
2-adrenergic receptors in potentiation.15,21
Therefore, in the present study, we were interested in examining
the interaction between PHA analog 1c and clonidine in antinoci-
ception in the absence and presence of receptor selective antago-
nists yohimbine, idazoxan or BU224.
It has been reported that pretreatment with endothelin ETA
receptor antagonists potentiated morphine and oxycodone antino-
ciception in rats and mice21,31 while fentanyl, tramadol and co-
deine antinociception was unaffected.15,32 Potentiation of
antinociception by endothelin ETA receptor antagonists was dem-
onstrated with l, d and j
-selective opioid agonists.33 Given these
results with other opioids, we were interested in studying the ef-
fect of endothelin ETA receptor antagonists on 1c antinociception.
In summary, the objectives of this study were to: (1) synthesize
and characterize PHA analog 1c; (2) determine the antinociceptive

646
S. V. Andurkar et al. / Bioorg. Med. Chem. Lett. 24 (2014) 644–648
O
O
S
O
H H
H H
N
H
N
N
O
CH3
Et3N/K2CO3/KI
(CH3CH2CO)2O
S
N
N
CH3CN, 75 oC, 5 h
N
Et3N, C6H6, 80oC
18 h
H
2
3
S
S
4
1c
Scheme 1. Synthesis of 1c.citrate.
A. Tail Flick
A. Tail Flick
9
8
7
6
5
4
3
2
1
0
Vehicle
10
9
8
7
6
5
4
3
2
1
0
Vehicle + 1c (0.9 mg/kg)
1c (0.1 mg/kg)
1c (0.3 mg/kg)
1c (0.9 mg/kg)
*#^
*
Naloxone + 1c (0.1 mg/kg)
Naloxone + 1c (0.3 mg/kg)
Naloxone + 1c (0.9 mg/kg)
*#^
*
*#^
*
*
*
*
*#^
*
*
*#^
*
*
*
*
*
0
30
60
90
120 180 240 300 360
0
30
60
90
120 180 240 300 360
Time (min)
Time (min)
B. Hot Plate
B. Hot Plate
22
20
18
16
14
12
10
26
*#^
*
Vehicle
Vehicle + 1c (0.9 mg/kg)
24
22
20
18
16
14
12
10
1c (0.1 mg/kg)
1c (0.3 mg/kg)
1c (0.9 mg/kg)
*#^
Naloxone + 1c (0.1 mg/kg)
Naloxone + 1c (0.3 mg/kg)
Naloxone + 1c (0.9 mg/kg)
*
*
*
*
*
*
*
*
90
0
30
60
90
120 180 240 300 360
0
30
60
120 180 240 300 360
Time (min)
Time (min)
Figure 2. Dose–response effect of 1c.citrate on antinociception in mice. Antinoci-
ceptive activity was determined using tail-flick (A) and hot-plate (B) tests. A dose-
dependent increase in antinociception was observed. Values are means S.E.M.;
n = 8 per group. ⁄P <0.05 compared to control (vehicle) group, #P <0.05 versus
0.1 mg/kg 1c.citrate, ^P <0.05 versus 0.3 mg/kg 1c.citrate.
Figure 3. Effect of naloxone on antinociception produced by 1c.citrate in mice.
Antinociceptive activity was determined using tail-flick (A) and hot-plate (B) tests.
Naloxone significantly blocked the antinociceptive effect of 1c.citrate. Values are
means S.E.M.; n = 8 per group. ⁄P <0.05 versus vehicle, #P <0.05 versus 0.1 mg/kg
1c.citrate, ^P <0.05 versus 0.3 mg/kg 1c.citrate.
antinociception. These results are consistent with previous reports
on 1a and 1b1,3 and suggest an overlapping mode of action for the
PHAs.
imidazoline receptors are not involved in 1c antinociception. These
results suggest that there may not be any physical or functional
interaction between 1c and the I2-imidazoline/a2-adrenergic
To assess the involvement of
receptors in 1c antinociception, mice were pretreated with
either with yohimbine 2-adrenergic antagonist), idazoxan
(I2-imidazoline/ 2-adrenergic antagonist) or BU224 (I2-imidazoline
antagonist) and then given 1c. Mice treated with vehicle produced
tail-flick and hot-plate latencies of about 2 s and 11.2 s, respec-
tively. Antinociception produced by 1c was not blocked by any of
a2-adrenergic, and I2 imidazoline
receptors in antinociception.
Synergistic antinociceptive interactions between clonidine and
morphine have been shown to occur at the spinal level.28,37 A de-
crease in antinociceptive potency of intrathecal morphine com-
pared to wild-type mice was noted in transgenic mice lacking
functional a2A adrenergic receptors, implying a direct interaction
between opioid and a2A adrenergic receptors.7 The morphine-
clonidine synergy was found to be mediated through N-type
(
a
a
the three antagonists (Fig. 4) indicating that
a2-adrenergic and I2

S. V. Andurkar et al. / Bioorg. Med. Chem. Lett. 24 (2014) 644–648
647
A. Tail Flick
A. Tail Flick
Vehicle + Vehicle
Vehicle + 1c (0.3 mg/kg)
10
9
8
7
6
5
4
3
2
1
0
9
8
7
6
5
4
3
2
1
0
Clonidine (0.9 mg/kg) + Vehicle
Vehicle + 1c (0.9 mg/kg)
Idazoxan + 1c (0.9 mg/kg)
BU 224 + 1c (0.9 mg/kg)
Yohimbine + 1c (0.9 mg/kg)
*
*
*#
*#
*
Clonidine (0.1 mg/kg) + 1c (0.3 mg/kg)
Clonidine (0.3 mg/kg) + 1c (0.3 mg/kg)
Clonidine (0.9 mg/kg) + 1c (0.3 mg/kg)
*
*
*
*
*
*
*
*
*
*
0
30
60
*
90 120 180 240 300 360
Time (min)
0
30
60
90
120 180 240 300 360
Time (min)
B. Hot Plate
24
22
20
18
16
14
12
10
B. Hot Plate
Vehicle + 1c (0.3 mg/kg)
Clonidine (0.9 mg/kg) + Vehicle
Clonidine (0.1 mg/kg) + 1c (0.3 mg/kg)
Clonidine (0.3 mg/kg) + 1c (0.3 mg/kg)
Clonidine (0.9 mg/kg) + 1c (0.3 mg/kg)
20
18
16
14
12
10
8
6
4
2
0
*
*
Vehicle + Vehicle
Vehicle + 1c (0.9 mg/kg)
Idazoxan + 1c (0.9 mg/kg)
BU 224 + 1c (0.9 mg/kg)
Yohimbine + 1c (0.9 mg/kg)
0
30 60 90 120 180 240 300 360
Time (min)
Figure 5. Effect of clonidine on 1c.citrate-induced antinociception in mice.
Antinociceptive activity was determined using tail-flick (A) and hot-plate (B) tests.
An additive effect was observed with clonidine plus 1c.citrate. Values are
means S.E.M.; n = 8 per group. ⁄P <0.05 compared to vehicle + 1c.citrate group
and #P <0.05 compared to a lower dose of clonidine.
0
30
60
90
120 180 240 300 360
Time (min)
Figure 4. Effect of idazoxan, BU224 and yohimbine on 1c.citrate antinociception in
mice. Antinociceptive activity was determined using tail-flick (A) and hot-plate (B)
tests. Idazoxan, BU224 and yohimbine did not block 1c.citrate antinociception.
Values are means S.E.M.; n = 8 per group. ⁄P <0.05 compared to vehicle treated
group.
224 (data not shown). Therefore, it can be concluded that no
significant interaction occurs between clonidine and 1c through
the I2-imidazoline/a2-adrenergic receptors in antinociception.
These results are in contrast to previous studies on other opioids.
Clonidine has been shown to potentiate morphine,21,25 oxyco-
done,21 tramadol,15 fentanyl,26 sufentanil,27 meperidine,40 and
other opioids. It is possible that 1c may behave like fentanyl in
many respects due to structural similarities. There are conflicting
calcium channels and picrotoxin sensitive G-proteins38 along with
p38 mitogen activated protein kinase (MAP kinase) and b-arrestin
-opioid and the a2A adren-
ergic receptors co-localize in hippocampal neurons where these
receptors form complexes that can be activated either by a -ago-
2.39 A subsequent report showed that
l
l
reports with regards to fentanyl-a2-adrenergic receptor interac-
nist or an a2A agonist, resulting in G-protein activation and an in-
crease in MAP kinase signaling.5 It was further understood that the
tions in antinociception. One study reports the potentiation of fen-
tanyl antinociception by clonidine.26 On the other hand, other
studies have demonstrated that fentanyl did not exhibit affinity
l-opioid and the a2A adrenergic receptors form a heterodimer in
brain neurons and communicate with each other via a conforma-
for the
unaffected in a2A adrenergic receptor knockout mice or in wild-
type mice pretreated with 2-adrenergic antagonists yohimbine
and atipamezole.14 Further, the
2-adrenoceptor has been shown
a
2-adrenergic receptor9 and fentanyl antinociception was
tional change that enables manipulation of one receptor by the
other.6 Thus, binding of morphine to the
l-opioid receptor causes
a
a conformational change in the norepinephrine-bound a2A adren-
a
ergic receptor that translates into inhibition of Gi G-protein activa-
tion and decreased MAP kinase signaling.6 The
l
-opioid-a2A
adrenergic receptor antinociceptive synergy has been shown to oc-
cur between numerous opioids and
2-adrenergic agonists.29,40
to sense the conformational changes induced by various ligands
differently.41 It is possible that the changes induced by 1c may
not be sensed by the
of potentiation.
a2A-adrenergic receptors, translating to a lack
a
Therefore, we were interested in assessing the effect of clonidine
on 1c antinociception in mice. Administration of the combination
of 1c (0.3 mg/kg, sc) plus clonidine (0.9 mg/kg, ip) resulted in a
slight increase in tail-flick and hot-plate latencies compared to
the administration of 1c (0.3 mg/kg, sc) or clonidine (0.9 mg/kg,
ip) alone (Fig. 5). Therefore, this could be characterized as a mild
additive effect as opposed to potentiation. Each drug probably pro-
duces its antinociceptive effect independent of the other and re-
sults in an overall increase in antinociceptive latencies. This mild
additive effect was not blocked by yohimbine, idazoxan or BU
Finally, the effect of endothelin-ETA receptor antagonist BQ123
on 1c antinociception was assessed. Pretreatment with endothelin
ETA receptor antagonists has been shown to potentiate mor-
phine,31 oxycodone21 antinociception and also antinociception
mediated by selective
l-, d- and j
-opioid agonists.33 It has been
shown that ETA receptor antagonists cause a reversal of morphine
tolerance by enhancing G-protein coupling.32,42,43 It is possible that
the same mechanisms may be involved in potentiation of opioid
antinociception by endothelin ETA receptor antagonists. We were

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S. V. Andurkar et al. / Bioorg. Med. Chem. Lett. 24 (2014) 644–648
interested in determining the effects of endothelin ETA receptor
antagonist BQ123 pretreatment on 1c antinociception. Our results
indicate (data not shown) that BQ123 pretreatment did not in any
way influence 1c antinociception in the mouse tail-flick and hot-
plate tests. Therefore we conclude that a functional link between
1c and endothelin ETA receptors does not exist in antinociception.
These results are consistent with those obtained previously with
fentanyl. Fentanyl antinociception was unaffected by pretreatment
with an endothelin ETA receptor antagonist.32 Although opioid
analgesics produce their antinociceptive effects by interacting with
opioid receptors, it is known that different opioid agonists can pro-
duce distinctly unique downstream events.44 This bias amongst
opioid agonists has been observed in terms of G protein coupling,
receptor phosphorylation, interactions with arrestins, receptor
desensitization, internalization and signaling. It is possible that
the unique interactions between 1c and opioid receptors may have
activated downstream events that do not functionally overlap with
the endothelin ETA receptor signaling pathways in antinociception.
This might explain the lack of potentiation of 1c antinociception by
endothelin ETA receptor antagonist BQ123.
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In conclusion, we report the synthesis, characterization and
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in a 10-fold increase in antinociceptive potency. The PHA analog 1c
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the absence of a functional link between 1c and endothelin ETA
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the antinociceptive effects of 1c in the mouse tail-flick and hot-
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a2-adrenergic receptors in PHA
antinociception as well as the lack of potentiation of PHA
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Funding for this project was provided by Midwestern University
Chicago College of Pharmacy. The authors express their sincere
thanks to Dr. Jeffrey A. Bjorklund, Professor of Chemistry, North
Central College, Naperville, IL for his assistance with NMR and IR
spectrometry and Dr. Mary Leonard, Midwestern University for
conducting some of the animal studies.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.11.
069.