The design and synthesis of a novel quinolizidine template for potent opioid and opioid receptor-like (ORL1, NOP) receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2003.09.068

A new class of high affinity opioid and opioid receptor-like receptor (ORL1 receptor, NOP receptor) ligands has been designed by conformational restriction of piperidine-based NOP receptor ligands, resulting in a novel quinolizidine scaffold. Different mo

Full text of DOI:10.1016/j.bmcl.2003.09.068

Bioorganic & Medicinal Chemistry Letters 14 (2004) 181–185
The design and synthesis of a novel quinolizidine template for
potent opioid and opioid receptor-like (ORL1, NOP)
receptor ligands
Ling Jong, Nurulain Zaveri* and Lawrence Toll
Biosciences Division, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025, USA
Received 28 June 2003; revised 20 September 2003; accepted 27 September 2003
Abstract—A new class of high affinity opioid and opioid receptor-like receptor (ORL1 receptor, NOP receptor) ligands has been
designed by conformational restriction of piperidine-based NOP receptor ligands, resulting in a novel quinolizidine scaffold. Dif-
ferent modifications of the pendant functional groups on the scaffold provide differential activities at the opioid and NOP receptors.
While the conformational rigidity will provide an improved understanding of the NOP and opioid receptor binding pockets, these
compounds also provide a new template for the design of novel opiate and NOP ligands.
#
2003 Elsevier Ltd. All rights reserved.
Nociceptin (NC, Orphanin FQ (N/OFQ)) is the endo-
genous ligand for the opioid receptor-like (ORL1)
peptides, the information is not sufficient to support
rational small-molecule NOP ligand design. Further-
more, the use of peptide ligands is plagued with inherent
limitations with respect to metabolic stability.
1
,2
receptor (now called the NOP receptor). Although
NOP/ORL1 is a member of the opioid receptor family,
and is a G-protein coupled receptor, it does not bind
opiates with high affinity. The NOP receptor and noci-
ceptin have been implicated in several physiological
Recently, several small-molecule NOP agonists and
1
9À25
antagonists have been reported in the literature
and
3
,4
pathways including pain, anxiety, and drug addiction.
A variety of studies have suggested that NOP agonists
patents (reviewed in ref 15). Several of these ligands
possess very high selectivity for the NOP receptor versus
other opioid receptors. For example, Kolczewski et al.
recently reported novel spiropiperidine-based pyrrolo-
pyrroles, of which compound 1 (Fig. 1) was identified as
5
may be useful clinically for treatment of anxiety, and
In addition,
6À8
antagonists may have analgesic activity.
various pharmacological and genetic manipulations
have indicated that this receptor and N/OFQ may also
a potent NOP agonist (K =0.49 nM) with >1000-fold
i
9
10
25
be involved in morphine tolerance, feeding, learning
1
selectivity over the m, d, and k opioid receptors. Simi-
1,12
13,14
and memory,
cardiovascular and renal systems,
larly, Kawamoto et al. disclosed a series of benzimida-
zole-based ligands of which J-113397 (Fig. 1) was
reported as a potent, selective NOP antagonist, with
among others. Therefore, development of highly selec-
tive and potent NOP ligands could provide new classes
of drugs for several human disorders.
21
>600-fold selectivity over the opioid receptors.
Since nociceptin is a 17-amino acid peptide, several
earlier studies have resulted in the identification of
modified N/OFQ-based peptide ligands for the NOP
receptor (reviewed in ref 15). Very selective peptide
agonists as well as antagonists have now been
It is interesting to note that all small-molecule NOP
ligands disclosed thus far contain a common piperidine
core and bear close structural resemblance to lofentanil
1
6À18
However, despite this enhanced under-
identified.
standing of the structural requirements of N/OFQ-like
*
Corresponding author. Tel.:+1-650-859-6041; fax:+1-650-859-3153;
e-mail: nurulain.zaveri@sri.com
Figure 1. Structures of some known NOP small-molecule ligands.
0
960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.09.068

182
L. Jong et al. / Bioorg. Med. Chem. Lett. 14 (2004) 181–185
and the anilidopiperidine class of opioid ligands.26 Most
of these reported ligands were discovered through high
throughput screening of large libraries and the resulting
hits were optimized for potency and selectivity versus
other opioid receptors by modifying the various
and J-2 reported by Kawamoto et al. that have sig-
2
1
nificantly different binding affinities (Fig. 2). J-1
exhibited low NOP affinity (IC =200 nM) and a 2-fold
5
0
higher affinity at the k receptor. Its affinity and selec-
tivity were improved by the addition of an a-methyl and
2-chloro groups to the N-benzyl substituent, which led
to J-2 (IC =5.9 nM and 8- and 5-fold selectivity versus
2
0,21
substituent groups on the central piperidine ring.
For example, the initial lead compound from which J-
13397 was developed, was J-1 (Fig. 2), a non-selective
5
0
1
m and k receptors). It is likely that the steric interactions
of these added substituents restricts the rotation of the
N-benzyl substituent to a smaller number of allowable
conformations, resulting in increased affinity and selec-
tivity. Computer-aided structural analysis of J-1 and J-2
revealed that J-1 has two low energy conformers, J-1A
and J-1B, with only 0.38 Kcal/mol of energy difference
(Fig. 2). This means the two conformations are almost
equally populated, whereas, J-2A is a more favorable
conformer, compared with J-2B, whose energy is 1.55
Kcal/mol higher. Therefore, the potent NOP activity of
J-2 may largely be due to the contribution of the global
low-energy conformer, J-2A.
1
25
lead with an IC of 200 nM for displacement of [ I]
5
0
Tyr1 nociceptin and with a 2-fold higher affinity at k
receptors. Introduction of a a-methyl and a 2-chloro
group in the N-benzyl substituent increased binding
affinity to NOP by about 33-fold (IC =5.9 nM), and
4
5
0
afforded a 8- and 5-fold selectivity versus m and k
receptors, respectively. Further modifications of the
piperidine nitrogen substituent further increased the
selectivity and resulted in a potent antagonist, J-
2
1
1
other small-molecule NOP agonists and antagonists like
13397. Similar approaches have been used to develop
2
0,23,24
Ro 64-6198, NNC 63-0532, and JTC-801.
At present, high-throughput screening coupled with
classical medicinal chemistry is still the most common
strategy for identification and development of small
molecule NOP agonists or antagonists. The discovery of
these selective NOP agonist and antagonists has affor-
ded a considerable opportunity to develop a high affi-
nity binding pharmacophore for the NOP receptor,
which can be used to accelerate future drug discovery.
Such a pharmacophore can also incorporate features
that afford selectivity for NOP versus other opioid
receptors. However, most known potent NOP ligands,
such as J-113397 and Ro 64-6198, are built around a
central piperidine core, and the greater mobility of their
piperidine N-substituents permits them to assume many
different positions in space. Such flexible molecules are
unlikely to provide useful information, because their
flexibility permits them to assume several possible low
energy conformations at the receptor site. We decided
to use conformational restriction around the piperidine
N-substitution to enhance the selectivity of these piper-
idine-based ligands for the NOP receptor. Such an
approach would also result in novel scaffolds that can
be a starting point to develop new classes of NOP
ligands not based on the piperidine core and give
further insight into the pharmacophore for high affi-
nity binding as well as selectivity versus other opioid
receptors.
We reasoned that conformational restriction of the low-
energy conformer of J-2 (viz. J-2A) could provide an
enhancement in affinity and perhaps selectivity, by
locking the piperidine N-substituent in a defined space
with respect to the piperidine ring. This would also
provide more definitive information about the spatial
and steric requirements at the NOP and opioid binding
pockets and result in a new scaffold. We designed the
rigid molecule, SR 14136 that mimics the low energy
conformers J-1A and J-2A. The N-a-methylbenzyl sub-
stituent was locked into a quinolizidine ring system,
such that the phenyl group of the N-substituent now
occupies a spatial position resembling that in J-1A and
J-2A (Fig. 2). Minor modifications of the functional
groups around this novel template (SR 14135–SR
14140) were also carried out and yielded interesting
results.
The target compounds (SR 14135–SR 14140) were syn-
thesized as shown in Scheme 1. A Robinson-type annu-
lation procedure was chosen for the key step in the
2
7
synthesis of the quinolizidine skeleton, as shown in
Scheme 1. The imino ether I-2 was obtained from read-
ily available I-1 in four steps: esterification, oxime
transformation, lactam formation, and imino ether
conversion. Reaction of I-2 with ethyl 3-oxo-4-penteno-
28
ate (Nazarov reagent) via Robinson-type annulation was
followed by stereospecifically reducing the tetrasubstituted
double bond to afford the trans-fused quinolizidine I-3
with equatorial phenyl and ethoxycarbonyl substituents
Our rational NOP ligand design was based on an SAR
analysis of the two structurally similar NOP ligands, J-1
Figure 2. Rational NOP ligand design.

L. Jong et al. / Bioorg. Med. Chem. Lett. 14 (2004) 181–185
183
.
Scheme 1. (a) SOCl
TsOH; (f) i-Bu AlH; (g) HCl (aq); (h) LiAlH
NaH, CH CH I; (n) H , PtO , CH CO H.
2
, CH
3
OH; (b) NH
2
OH HCl, NaOAc, CH
3
OH; (c) H
2
, 5% Pd/C, CH
3
CO
2
OH; (d) Me
2
SO
4
; (e) ethyl 3-oxo-4-pentenoate, p-
; (i) 2-fluoronitrobenzene; (j) Column separation; (k) H , 10% Pd/C; (l) 1,1-carbonyldiimidazole; (m)
3
4
2
3
2
2
2
3
2
3
at C-6 and C-1, respectively. The stereochemistry of I-3
was confirmed by NOE (nuclear Overhauser effect)
experiments. Subsequent decarboxylation of I-3 led to
the 2-ketoquinolizidine I-4, which was then converted to
the amine I-5 obtained as a C-2 diastereomeric mixture.
The coupling of I-5 and 2-fluoronitrobenzene was fol-
lowed by chromatographic separation to yield I-6 and I-
DPDPE, and [ H] U69593 for the m, d, and k receptors,
32
respectively. Functional activity of these compounds
3
5
was determined by stimulation of [ S] GTPgS binding
to cell membranes, as we have described previously.
1
6,32
Binding affinities and functional activity are shown in
Table 1.
7
genation of I-6 and I-7 followed by cyclization afforded
with the relative stereochemistry indicated. Hydro-
Among the diastereomeric pairs, in each case, the
equatorial diastereoisomer (SR 14136, SR 14138, and
SR 14140) was found to have higher affinity than the
corresponding axial diastereoisomer (SR 14135,
SR 14137, and SR 14139) by one to two orders of
magnitude at all four receptors. SR 14136 was found to
be the most potent compound in this series, and had
NOP binding affinity very comparable to J-2. However,
it also has high affinity for m and k, indicating that the
conformational restriction also provides favorable
binding for the m and k receptors. None of the com-
pounds synthesized had significant affinity at the d
opioid receptor. Addition of an ethyl group to the N-
benzimidazolinyl moiety significantly decreases affinity
at k but also at NOP, while maintaining m affinity.
Saturation of the pendant phenyl ring as in SR 14140
(corresponding to the piperidine N-benzyl substituent in
J-2) leads to a significant decrease in affinity at m, with a
slight decrease at NOP while maintaining k affinity.
Thus, minor modifications of this template can
2
1
SR 14135 and SR 14136, respectively, which were
further converted to SR 14137 and SR 14138 by N-
ethylation. The final target compounds were character-
2
9
ized by NMR and mass spectrometry. NOE confirmed
that SR 14136 possessed equatorial C-2 and C-6 sub-
stituents, whereas SR 14135 has an axial C-2 benzimi-
dazolinyl moiety and an equatorial C-6 phenyl group.
SR 14139 and SR 14140 were similarly converted from
I-8, which was produced from I-5 by platinum-catalyzed
3
0
hydrogenation,
using the same synthetic routes
described for SR 14135 and SR 14136.29
These new quinolizidine-based ligands were tested for
binding affinity at human NOP receptors, and human m-,
d-, and k-opioid receptors, all transfected into CHO
3
cells. Binding to NOP was conducted with [ H] N/OFQ,
3
1
as described previously. Binding to the opioid recep-
3
3
tors utilized the selective agonists [ H] DAMGO, [ H] Cl-
Table 1. Structure–activity relationships of the quinolizidine class of ORL ligandsa
Compd
Receptor binding
(nM)
[35S]GTPgS binding
K
i
NOP
m
k
NOP
m
k
d
EC50
% Stim.
EC50
% Stim.
EC50
%Stim.
SR 14135
SR 14136
SR 14137
SR 14138
SR 14139
SR 14140
N/OFQ
786Æ302
5.7Æ0.1
47.7Æ0.5
5.24Æ0.52
17.6Æ1.0
2.54Æ0.2
119Æ11
271Æ16
1.1Æ0.35
987Æ300
22.7Æ3.6
227Æ99
2.3Æ0.1
>10,000
1720Æ670
1838Æ709
1492Æ746
>10,000
>10,000
65Æ30
>10,000
198Æ22
>10,000
105Æ23
>10,000
>10,000
>10,000
4.7Æ1.4
>10,000
210Æ1
89Æ4
87Æ7
55Æ13
83Æ2
100Æ11
79Æ8
535Æ332
19.6Æ3.8
189Æ20
>10,000
165Æ66
>10,000
678Æ206
4.0Æ0.1
>10,000
20.9Æ1.8
28.7Æ5.9
0.06Æ0.01
46.8Æ2.6
2075Æ1037
51Æ13
43Æ5
100
a
Receptor binding and [35S]GTPgS binding were conducted as described previously.16,31
), where [L] (the concentration of the radioligand) is approximately 0.2, 1.9, 1.1, and 1.2 nM for NOP, m, k, and d binding, respectively. Each
experiment was conducted a minimum of twice in triplicate. An EC50 value of >10,000 for [ S]GTPgS binding could indicate either low affinity or
lack of agonist activity.
i i
K values were derived from the equation K =IC50/(1+[L]/
K
d
35

184
L. Jong et al. / Bioorg. Med. Chem. Lett. 14 (2004) 181–185
modulate the binding affinity and selectivity for NOP
versus opioid receptors.
4. Calo, G.; Rizzi, A.; Bigoni, R.; Guerrini, R.; Salvadori,
S.; Regoli, D. Clin. Exp. Pharmacol. Physiol. 2002, 29,
2
23.
5
. Jenck, F.; Wichmann, J.; Dautzenberg, F. M.; Moreau,
J. L.; Ouagazzal, A. M.; Martin, J. R.; Lundstrom, K.;
Cesura, A. M.; Poli, S. M.; Rover, S.; Kolczewski, S.;
Adam, G.; Kilpatrick, G. Proc. Natl. Acad. Sci. U.S.A.
Functional activity studies suggest that compounds
SR 14136 and SR 14138 are full agonists at the NOP
receptor. Intriguingly, SR 14136 is a very potent k ago-
nist (Table 1), being nearly 10 times more potent than
the standard k agonist U69593 (data not shown).
Saturation of the pendant phenyl ring as in SR 14140
lowers efficacy at both NOP and k, and completely abol-
ishes efficacy at m receptors. This trend toward decreased
agonist efficacy with saturated N-substituents is similar to
the results of Kawamoto et al. where they observe ago-
nist activity for compounds J-1 and J-2, which contain
the aromatic N-benzyl substituent, but find antagonist
activity with compounds bearing cycloalkyl substituents
at the piperidine nitrogen as in J-113397.
2
000, 97, 4938.
6
. Di Giannuario, A.; Rizzi, A.; Pieretti, S.; Guerrini, R.;
Bertorelli, R.; Salvadori, S.; Regoli, D.; Calo, G. Neuro-
sci. Lett. 2001, 316, 25.
7. Calo, G.; Rizzi, A.; Rizzi, D.; Bigoni, R.; Guerrini, R.;
Marzola, G.; Marti, M.; McDonald, J.; Morari, M.;
Lambert, D. G.; Salvadori, S.; Regoli, D. Br. J. Pharma-
col. 2002, 136, 303.
2
1
8
. Yamada, H.; Nakamoto, H.; Suzuki, Y.; Ito, T.; Aisaka,
K. Br. J. Pharmacol. 2002, 135, 323.
9
. Lutfy, K.; Hossain, S. M.; Khaliq, I.; Maidment, N. T.
Br. J. Pharmacol. 2001, 134, 529.
1
0. Polidori, C.; de Caro, G.; Massi, M. Peptides 2000, 21,
051.
Although our novel quinolizidine template does not
provide a selective NOP ligand, our results clearly indi-
cate that appropriate structural modifications of this
new template can yield selective ligands. This con-
formationally rigid template will give further insight into
the binding pockets of the NOP and opioid receptors.
1
11. Sandin, J.; Georgieva, J.; Schott, P. A.; Ogren, S. O.;
Terenius, L. Eur. J. Neurosci. 1997, 9, 194.
12. Manabe, T.; Noda, Y.; Mamiya, T.; Katagiri, H.; Hou-
tani, T.; Nishi, M.; Noda, T.; Takahashi, T.; Sugimoto,
T.; Nabeshima, T.; Takeshima, H. Nature 1998, 394, 577.
1
1
3. Kapusta, D. R. Peptides 2000, 21, 1081.
4. Kapusta, D. R.; Kenigs, V. A. Am. J. Physiol. 277, R987,
It is noteworthy that SR 14136 is a high affinity, potent
k agonist. It has been generally assumed that a selective
k agonist would be a powerful analgesic agent without
the respiratory, gastrointestinal and addictive side
effects of m-based opioids. Most synthetic k agonists fall
into two main structural classes: the benzomorphans
1
5. Zaveri, N. Life Sci. 2003, 73, 663.
6. Dooley, C. T.; Spaeth, C. G.; Berzetei-Gurske, I. P.;
Craymer, K.; Adapa, I. D.; Brandt, S. R.; Houghten,
R. A.; Toll, L. J. Pharmacol. Exp. Ther. 1997, 283, 735.
999.
1
1
17. Judd, A. K.; Kaushanskaya, A.; Tuttle, D. J.; Sanchez, A.;
Khroyan, T.; Polgar, W.; Toll, L. J. Peptide Res. 2003, 62,
(bremazocine, ethylketocyclazocine) and the arylaceta-
mides (U-50488). On the other hand, it has been sug-
1
91.
1
1
8. Calo, G.; Rizzi, A.; Rizzi, D.; Bigoni, R.; Guerrini, R.;
Marzola, G.; Marti, M.; McDonald, J.; Morari, M.;
Lambert, D. G.; Salvadori, S.; Regoli, D. Br. J. Pharma-
col. 2002, 136, 303.
9. Wichmann, J.; Adam, G.; Rover, S.; Cesura, A. M.;
Dautzenberg, F. M.; Jenck, F. Bioorg. Med. Chem. Lett.
gested that k-selective antagonists could provide a long-
lasting drug abuse treatment strategy.33 We have shown
that modifications of the pendant groups of our novel
template can modulate agonist efficacy (compare
SR 14136 and SR 14140). Thus, this quinolizidine tem-
plate now offers a new scaffold to develop selective k
receptor-based agonists and antagonists. Work is cur-
rently underway in our laboratory to explore the
potential of this novel series of opioid ligands.
1
999, 9, 2343.
20. Rover, S.; Adam, G.; Cesura, A. M.; Galley, G.; Jenck,
F.; Monsma, F. J., Jr.; Wichmann, J.; Dautzenberg, F. M.
J. Med. Chem. 2000, 43, 1329.
2
1. Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.;
Nakashima, H.; Kato, T.; Ohta, H.; Iwasawa, Y. J. Med.
Chem. 1999, 42, 5061.
Acknowledgements
2
2
2
2
2. Rover, S.; Wichmann, J.; Jenck, F.; Adam, G.; Cesura,
A. M. Bioorg. Med. Chem. Lett. 2000, 10, 831.
3. Thomsen, C.; Hohlweg, R. Br. J. Pharmacol. 2000, 131,
We thank Ms. Willma Polgar for expert technical assis-
tance. This work was supported by NIDA grant
DA06682 to L.T. Partial support from NIDA grant
DA14026 to N.Z. is also acknowledged.
9
03.
4. Shinkai, H.; Ito, T.; Iida, T.; Kitao, Y.; Yamada, H.;
Uchida, I. J. Med. Chem. 2000, 43, 4667.
5. Kolczewski, S.; Adam, G.; Cesura, A. M.; Jenck, F.;
Hennig, M.; Oberhauser, T.; Poli, S. M.; Rossler, F.;
Rover, S.; Wichmann, J.; Dautzenberg, F. M. J. Med.
Chem. 2003, 46, 255.
References and notes
2
2
6. Maguire, P.; Tsai, N.; Kamal, J.; Cometta-Morini, C.;
Upton, C.; Loew, G. Eur. J. Pharmacol. 1992, 213, 219.
7. Trost, B. M.; Kunz, R. A. J. Am. Chem. Soc. 1975, 97,
1
2
3
. Meunier, J. C.; Mollereau, C.; Toll, L.; Suaudeau, C.;
Moisand, C.; Alvinerie, P.; Butour, J.-L.; Guillemot, J.-
C.; Ferrara, P.; Monsarrat, B.; Mazarguil, H.; Vassart,
G.; Parmentier, M.; Costentin, J. Nature 1995, 377, 532.
. Reinscheid, R. K.; Nothacker, H. P.; Bourson, A.; Ardati,
A.; Henningsen, R. A.; Bunzow, J. R.; Grandy, D. K.;
Langen, H.; Monsma, F. J., Jr.; Civelli, O. Science 1995,
7
8. Trost, B. M.; Kunz, R. A. J. Org. Chem. 1974, 39, 2648.
152.
2
2
9. Overall yields of the final compounds were between 5 and
1
0%. All final compounds were isolated as free bases and
were characterized by NMR and mass spectrometry.
NMR was carried out on a Varian 300 MHz NMR and
mass spectrometry on a Finnigan LCQ DUO LC/MS/MS
270, 792.
. Calo, G.; Guerrini, R.; Rizzi, A.; Salvadori, S.; Regoli, D.
Br. J. Pharmacol. 2000, 129, 1261.

L. Jong et al. / Bioorg. Med. Chem. Lett. 14 (2004) 181–185
185
1
system with an electrospray ionization (ESI) probe. SR
SR 14139: H NMR (300 MHz, CDCl
21H), 2.05 (m, 1H), 2.20 (m, 1H), 2.41 (m, 1H), 3.35 (m,
3
) d 1.00–2.00 (m,
1
1
2
1
4135: H NMR (300 MHz, CDCl ) d 1.40–1.95 (m, 9H),
3
.15–2.45 (m, 3H), 2.85 (m, 1H), 3.00 (dd, 1H), 4.42 (m,
H), 7.00–7.15 (m, 3H), 7.20–7.45 (m, 6H), 9.5 (br.s, 1H,
1H), 4.40 (m, 1H), 7.00–7.15 (m, 3H), 7.30 (m, 1H), 9.65
+
31 3
(br.s, 1H, NH). ES–MS for C22H N O: 354.3 (M +H).
+
1
NH). ES–MS for C H N O: 348.2 (M +H). SR 14136:
2
SR 14140: H NMR (300 MHz, CDCl ) d 1.00–2.20 (m,
2
25
3
3
1
H NMR (300 MHz, CDCl ) d 1.45–1.95 (m, 8H), 2.20–
19H), 2.35 (m, 2H), 2.65 (m, 2H), 2.85 (m, 1H), 3.12 (m,
1H), 4.61 (m, 1H), 7.05 (m, 3H), 7.30 (m, 1H), 9.05 (br.s,
1H, NH). ES–MS for C22H N O: 354.2 (M +H).
31 3
3
2.40 (m, 2H), 2.55 (m, 1H), 2.70 (m, 1H), 3.00 (m, 1H),
+
3.43 (dd, 1H), 4.52 (m, 1H), 7.00–7.15 (m, 4H), 7.20–7.45
(
3
m, 5H), 9.30 (br.s, 1H, NH). ES–MS for C H N O:
2
48.2 (M +H). SR 14137: H NMR (300 MHz, CDCl )
3
30. Schuda, P. F.; Greenlee, W. J.; Chakravarty, P. K.;
Eskola, P. J. Org. Chem. 1988, 53, 873.
2
25
3
+
1
d 1.30 (t, 3H), 1.40–1.95 (m, 9H), 2.20–2.40 (m, 3H), 2.85
m, 1H), 2.98 (dd, 1H), 3.95 (q, 2H), 4.45 (m, 1H), 6.95–
31. Adapa, D. I.; Toll, L. Neuropeptides 1997, 31, 403.
32. Toll, L.; Berzetei-Gurske, I. P.; Polgar, W. E.; Brandt,
S. R.; Adapa, I. D.; Rodriguez, L.; Schwartz, R. W.;
Haggart, D.; O’Brien, A.; White, A.; Kennedy, J. M.;
Craymer, K.; Farrington, L.; Auh, J. S. NIDA Res.
Monogr. 1998, 178, 440.
(
7
3
.10 (m, 3H), 7.20–7.45 (m, 6H). ES–MS for C H N O:
24 29 3
76.2 (M +H). SR 14138: H NMR (300 MHz, CDCl )
3
+
1
d 1.30 (t, 3H), 1.40–1.95 (m, 8H), 2.20 (m, 1H), 2.30 (m,
1
1
7
H), 2.50 (m, 1H), 2.65 (m, 1H), 3.00 (m, 1H), 3.40 (m,
H), 3.95 (q, 2H), 4.50 (m, 1H), 6.95–7.15 (m, 4H), 7.20–
.41 (m, 5H). ES–MS for C24H N O: 376.2 (M +H).
29 3
33. Zimmerman, D. M.; Leander, J. D. J. Med. Chem. 1990,
33, 895.
+