Synthesis and structure-activity relationships of 4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: Part 1

Article abstract of DOI:10.1016/j.bmcl.2007.03.061

A series of 4-hydroxy-4-phenylpiperidines have been synthesized and bind to the nociceptin receptor with high affinity. The synthesis and structure-activity relationships at the N-1 and C-4 are described.

Full text of DOI:10.1016/j.bmcl.2007.03.061

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3023–3027
Synthesis and structure–activity relationships of 4-hydroxy-
4-phenylpiperidines as nociceptin receptor ligands: Part 1
Ginny D. Ho,a,* Ana Bercovici,a Deen Tulshian,a William J. Greenlee,a Ahmad Fawzi,b
April Smith Torhanb and Hongtao Zhangb
aDepartment of Chemical Research—CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth,
NJ 07033, USA
bDepartment of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 31 January 2007; revised 14 March 2007; accepted 19 March 2007
Available online 23 March 2007
Abstract—A series of 4-hydroxy-4-phenylpiperidines have been synthesized and bind to the nociceptin receptor with high affinity.
The synthesis and structure–activity relationships at the N-1 and C-4 are described.
Ó 2007 Elsevier Ltd. All rights reserved.
Following the discovery of the nociceptin receptor, there
has been remarkable progress toward understanding its
pharmacological relevancy. The nociceptin receptor,
NOP (previously termed ORL-1 (opioid receptor-like-1)
or OP4), was cloned as an ‘orphan receptor’ in 1994.1
It is a member of the G protein-coupled receptor
(GPCR) superfamily and is widely distributed through-
out the brain and spinal core. The nociceptin receptor
expresses ꢀ50% sequence homology to the classic d, j,
and l opioid receptors (DOP, KOP, and MOP, respec-
tively). Even with this degree of homology, the nocicep-
tin receptor has low affinity for the endogenous opioid
peptides and synthetic opioid receptor ligands. Its
endogeneous ligand, nociceptin (or orphanin FQ), is a
17-amino acid neuropeptide isolated from the brain in
1995,2 which also exhibits high structural similarities
to the known opioid peptides, particularly dynorphin,
but fails to activate the classic opioid receptors. There-
fore, the nociceptin receptor is pharmacologically
distinct from the classic opioid receptors. Since the noci-
ceptin receptor is widely distributed throughout the ner-
vous system, it may participate in a broad spectrum of
pharmacological processes. Intensive pharmacological
studies with the nociceptin receptor and its peptide
ligand and analogs over the past several years have
resulted in significant advances in understanding the
interaction of nociceptin with biological systems. In
our in-house studies, either central (ICV) or peripheral
(iv) administration of nociceptin in conscious guinea
pigs produces inhibition of capsaicin-induced cough.3
Other accounts also demonstrate that the nociceptin/
NOP system may play important roles in the regulation
of urinary incontinence, pain, stress and anxiety, feed-
ing, learning and memory, locomotor activity, substance
abuse, cardiovascular function, sleep disturbance, and
Parkinson’s disease.4
High-throughput screening of the Schering compound
collection has identified a number of hits with varying
affinities for the nociceptin receptor. In this report, we
disclose our early SAR studies based on the 4-hydro-
xy-4-phenyl piperidine scaffold. 4-Hydroxy-4-phenyl
piperidines have been investigated extensively in the lit-
erature and are key moieties in a variety of biologically
active compounds. The piperidine framework has also
been reported in a number of small molecule nociceptin
receptor ligands.5 Our initial lead in this series is com-
pound 1 with affinity for the nociceptin receptor of
613 nM. Initial SAR development focuses on substitu-
tion of the piperidine nitrogen in order to determine
the optimal linker between the piperidine nitrogen and
the phenyl (Table 1). Comparison of compounds 3, 4,
and 6 indicates that the benzyl analog 6 exhibits the
highest affinity for the nociceptin receptor. Branching
at the a-position to the piperidine nitrogen (cf. 4 and 5)
Keywords: Nociceptin/orphin FQ; Nociceptin receptor (NOP); Opioid
receptor-like-1 (ORL-1); Opioid receptors (MOP, KOP, DOP);
G protein-coupled receptor.
*
Corresponding author. Tel.: +1 908 740 3502; fax: +1 908 740
7152; e-mail: ginny.ho@spcorp.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.061

3024
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3023–3027
Table 1. Nociceptin receptor binding of 2
O
Ph OR
Ph OH
Br
OH
Ph
b
c
a
Ph
Ph
N
N
N
N
R
11
Ph
Ph
Ph
Ph
Ph
Ph
2
12
13
14
Compound -R
NOP Ki
(nM)a (% inh,
at 10 lM)
MW
CLogP
Scheme 2. Reagents: (a) 4-piperidone monohydrate hydrochloride,
K2CO3ÆMeCN; (b) PhLi or PhMgBr, THF; (c) NaH, RI, DMF.
Ph
Ph
1
3
4
5
613
371.51 4.9
295.42 3.46
281.39 3.07
295.42 3.56
267.37 2.94
nation of the corresponding alcohol with thionyl chlo-
ride or thionyl bromide, respectively. The alcohols are
either purchased or prepared by reduction of the corre-
sponding ketones of type 7 with sodium borohydride or
reaction of the aldehydes of type 8 with an appropriate
lithium or Grignard reagent. Compounds of type 10 are
obtained by alkylation of 4-hydroxy-4-phenyl piperidine
hydrochloride with the chloride or bromide intermedi-
ates of type 9a or 9b in acetonitrile in the presence of
potassium carbonate with or without sodium iodide.
Ph
(60%)
(46%)
Ph
Ph
(82%)
Me
Compounds of type 14, containing an ether substituent,
are synthesized as described in Scheme 2. Alkylation of
4-piperidone hydrochloride with bromodiphenylme-
thane (11) produces the 4-piperidone intermediate 12.
Treatment of 12 with phenyl lithium or phenyl magne-
sium bromide yields 13. Reaction of 13 with sodium hy-
dride and an appropriate alkyl iodide provides
compounds of type 14.
6
1983 (75%)
Ph
a Values are means of at least two experiments.
or introduction of an additional phenyl group a to the
phenyl (cf. 1 and 3) enhances the affinity at the nocicep-
tin receptor. Since the benzyl analog 6 displays a better
overall profile including the potency and physical prop-
erties (highlighted in bold), it is selected for further opti-
mization. The extended study on compound 6 centers on
evaluating benzylic substitution.
Target compounds are tested for their affinity at the
cloned human nociceptin receptor expressed in CHO cell
membranes by measuring their ability to compete with
[
125I][Tyr14]nociceptin FQ. The opioid receptor binding
assays are performed with CHO cell membranes
expressing the human opioid receptors using [3H]-dipre-
norphine as the radioligand. The Ki values have been
determined from dose–response curves. The functional
activities of these compounds are evaluated as their abil-
ity to enhance the binding of [35S]GTPcS in the presence
of GDP, using membranes isolated from cells transfec-
ted with the nociceptin receptor.6
OH
OH
Ph
Ph
4
N
N
R
1
Ph
2
Ph
NOP Ki= 613 nM
1
Table 2 details the effect of substitution on the benzylic
carbon of compound 6. In general, introduction of a
substitution at the benzylic position leads to an increase
of potency with the exception of 24 and 27–29. Addition
of an alkyl substituent containing three to six carbons
produces potent NOP ligands with 2- to 19-fold selectiv-
ity over the MOP receptor. We found that the four-car-
bon linear chain is optimal (18, Ki = 5 nM, and 20,
Ki = 9 nM). Introduction of a benzyl group provides
good affinity toward NOP and displays partial agonist
response (compound 23). Introduction of the hydroxy-
methyl group in 24 produces a substantial loss of
potency. However, potency is enhanced by converting
the hydroxyl analog 24 to the corresponding methyl
ether 25 or ethyl ether 26. The phenyl analog 13 shows
a dramatic improvement in affinity toward NOP, mod-
erate selectivity over KOP and MOP, and excellent
selectivity over DOP (highlighted in bold). Replacement
of one of the phenyls in 13 with a pyridine leads to
Scheme 1 outlines the general routes for preparing 4-hy-
droxy-4-phenylpiperidine analogs of type 10. The chlo-
ride and bromide intermediates of type 9a or 9b are
either purchased or prepared by bromination or chlori-
O
X
Ph OH
R
Z
a, b
X
d
R
7
N
X
c, b
R
O
X
9a, Z= Cl
9b, Z= Br
H
10
8
Scheme 1. Reagents and condition: (a) NaBH4, MeOH; (b) SOCl2 or
SOBr2, CH2Cl2; (c) RLi or RMgBr, THF; (d) 4-hydroxy-4-
phenylpiperidine hydrochloride, K2CO3, NaI (Z = Cl), MeCN, 80 °C.

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3023–3027
Table 2. SAR of the benzylic modification analogs
3025
Ph OH
N
R
Compounda
R
Ki (nM)b
NOP
1983
DOP
nd
KOP
nd
MOP
6
15
16
17
18
19
20
21
22
23
24
25
26
27
28
H
nd
Me
323
135
19
33,110
20,890
4126
441
4149
1427
245
36
6265
2298
341
29
Et
n-Pr
n-Bu
5
n-Pent
i-Pent
n-Hex
c-Pent
CH2Ph
CH2OH
CH2OMe
CH2OEt
CO2Me
CN
14
184
220
185
335
312
288
nd
37
9
348
125
144
787
24
18
550
41
5323
187
16
4035
295
134
1887
10,000
nd
nd
32,960
15,250
121,800
nd
1771
1028
6753
nd
780
451
59,810
nd
F
H
N
29
13
8183
22295
4381
3736
O
F
Ph
13
1666
364
233
30
31
32
2-Pyridinyl
3-Pyridinyl
2-Thienyl
214
323
35
21,890
10,920
7845
5935
2993
971
9324
819
405
a All compounds are racemates except for 6 and 13.
b Values are means of at least two (nd, not determined).
Table 3. Functional activity of selected benzylic modification analogs
decreases in potency (30 and 31). Substitution of a 2-thi-
ophene at the benzylic position of 6 yields a potent NOP
ligand 32 with 11.5-fold selectivity over MOP and
excellent selectivity over DOP. Introduction of an
electron withdrawing substituent results in significant
decreases or loss in the affinity at the NOP receptor
(27–29). Table 3 shows the functional activity of
compounds of type 10 (X = H) that have NOP binding
affinity less than 20 nM.
Compound
R
GTPcS % Stim at (lM)
13
17
18
19
20
21
23
Ph
n-Pr
107 at 10
99 at 10
102 at 1
101 at 10
74 at 10
117 at 10
49 at 100
n-Bu
n-Pent
i-Pent
n-Hex
Bn
Encouraged by the potency and selectivity of compound
13, we then examined variations of the aromatic substi-
tution pattern in 13. A variety of substituents have been
introduced on one or both of the phenyl rings of the
benzhydryl moiety. The receptor binding data for the
benzhydryl modifications are summarized in Table 4.
It appears that nociceptin receptor binding affinities
are influenced by the substitution pattern. With the
exception of 50, addition of substituents to the ortho po-
sition of one or both of the phenyls of the benzhydryl
yields analogs with improved potency. Introduction of
a methyl at the ortho position produced a potent NOP
agonist 33 with greater than 400-fold selectivity over
DOP and KOP, and greater than 100-fold selectivity

3026
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3023–3027
Table 4. SAR of the benzhydryl modification analogs
Ph OH
N
X
Y
Compounda
X
Y
Ki (nM)b
NOP
DOP
KOP
MOP
13
33
H
H
13
2
1666
969
364
802
233
246
35
H
2-Me
2-Me
2-Me
3-Me
4-Me
2-CF3
3-CF3
4-CF3
2-Et
(À)34
(+)35
36
H
0.7
23
3
503
295
H
8765
2437
9365
1271
7355
10,124
237
1205
1095
2687
1362
6621
4294
535
361
147
3728
127
714
1207
9
H
37
38
H
53
12
357
225
0.6
4
H
39
40
H
H
41
42
H
H
2-Cl
3-Cl
1674
3029
1431
2945
2110
4458
975
1136
1971
164
609
201
793
177
170
2449
28
43
44
H
26
132
5
H
4-Cl
2-F
45
46
H
1479
1144
2443
519
H
2-Br
4-Br
11
125
1
47
48
H
H
2-OMe
2-CH2OH
2-CO2H
2-Me
2-Cl
49
50
H
9
1977
>100,000
5791
1665
1783
584
1174
8057
1712
635
120
2864
2147
256
148
183
nd
H
6753
4
51
52
2-Me
2-Cl
2-F
4-F
2-Br
2-OMe
4-OMe
2
53
54
2-F
4-F
6
1172
123
42
21
3
55
56
2-Br
2-OMe
4-OMe
nd
nd
306
18160
13715
8287
302
843
843
758
126
57
58
439
325
155
2878
17
(CH2)0
(CH2)2
59
381
a Compounds 33–50 are racemates except for (À)34 and (+)35.
b Values are means of at least two experiments (nd, not determined).
over MOP. Compound 33 displays an agonist response
with an EC50 of 29 nM. The resolution of racemic 33
has been completed in order to determine the effect of
stereochemistry on nociceptin receptor binding. The
(À)-isomer 34 is more potent toward the NOP receptor
and more selective over the MOP receptor than the (+)-
isomer 35 and also produces a higher agonist response.
The 2-ethyl analog 41 is highly potent, but without im-
proved selectivity. Introduction of a trifluoromethyl, fluo-
rine, chlorine, bromine, methoxy or hydroxymethyl at the
ortho position of one or both of the phenyls provides
excellent affinity for NOP, excellent selectivity over
DOP and KOP, and moderate to excellent selectivity over
MOP (38, 42, 45, 46, 48, 49, 51–53, and 56). We observe
that moving the substitution from the ortho to the para
position of the phenyl(s) decreases the affinity for NOP
(cf. 33 and 37, 38 and 40, 42 and 44, 46 and 47, 53 and
54, 56 and 57). Introduction of a conformationally re-
stricted substituent at the piperidine nitrogen reduces
the affinity at the NOP receptor (58 and 59). The 9-flu-
orenyl analog 58 exhibits high affinity for the KOP and
little affinity for DOP. The dibenzosuberyl analog 59 has
comparable affinities toward NOP and MOP. Table 5
summarizes the functional activity of the benzhydryl
modification analogs when the nociceptin receptor
Table 5. Functional activity of selected benzhydryl modification
analogs
Compound
GTPcS % Stim at [lM] (EC50)
33
(À)34
(+)35
36
107 at 0.1 (29 nM)
101 at 1 (23 nM)
94 at 10 (331 nM)
87 at 10
38
42
106 at 1
105 at 10
45
46
104 at 10
127 at 10
48
49
100 at 10 (26 nM)
122 at 10
51
52
95 at 10 (114 nM)
103 at 100 (222 nM)
98 at 10
53
56
107 at 1 (117 nM)

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3023–3027
Table 6. SAR of the hydroxy modification analogs
Ph OR
3027
Acknowledgment
The authors thank Drs. Michael Czarniecki, Ashit Gan-
guly, Michael Graziano, John Piwinski, and Catherine
Strader for the helpful discussion.
N
References and notes
Compound
R
Kia (nM)
DOP KOP
364
1. (a) Mollereau, C.; Parmentier, M.; Mailleux, P.; Butour, J.;
Moisand, C.; Chalon, P.; Caput, D.; Vassart, G.; Meunier,
J.-C. FEBS Lett. 1994, 341, 33; (b) Fukada, K.; Kato, S.;
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Houtani, T.; Sugomoto, T. FEBS Lett. 1994, 343, 42; (c)
Chen, Y.; Fan, Y.; Liu, J.; Mestek, A.; Tian, M.; Kozak, C.
A.; Yu, L. FEBS Lett. 1994, 347, 279; (d) Wang, J. B.;
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Eppler, C. M.; Uhl, G. R. FEBS Lett. 1994, 348, 75.
2. (a) 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.;
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NOP
MOP
233
13
60
61
62
63
H
13
54
1666
2651
898
Me
Et
343
488
412
377
59
72
n-Pr
Bn
2767
3741
1484
13,390
1649
21,455
162
a Values are means of two–three experiments (nd, not determined).
Table 7. Functional activity of the hydroxy modification analogs
Compound
R
GTPgS % Stim at (lM)
60
61
62
63
Me
Et
109 at 100
104 at 100
96 at 100
86 at 100
n-Pr
Bn
3. (a) Mcleod, R. L.; Parra, L. E.; Mutter, J. C.; Erickson, C.
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affinity is less than 20 nM. All of these compounds dis-
play a good agonist response.
Extended SAR work on compound 13 has centered on
evaluating the C-4 hydroxy modification (Table 6). It
appears that an alkoxy substitution is tolerated at the
C-4 position of the piperidine. Increasing the size of
the substituent on the oxygen decreases the affinity
and the agonist response at the nociceptin receptor
(Table 7).
In summary, we have successfully identified a series of
N-benzhydryl-substituted 4-hydroxy-4-phenylpiperidines
as potent nociceptin receptor ligands. Introduction of a
small substitution at the ortho position of one or both of
the phenyl rings of the benzhydryl moiety provides
excellent affinity and agonist response for the nociceptin
receptor. Additional studies of nociceptin receptor
agonists based on this scaffold will be reported in due
course.
5. (a) Zaveri, N.; Jiang, F.; Olsen, C.; Polgar, W.; Toll, L. AAPS
J. 2005, 7, E345, and references cited therein; (b) Chen, Z.;
Goehring, R. R.; Valenzano, K. J.; Kyle, D. J. Bioorg. Med.
Chem. Lett. 2004, 14, 1347, and references cited therein.
6. Fawzi, A. B.; Zhang, H.; Weig, B.; Hawes, B.; Graziano,
M. P. Eur. J. Pharmacol. 1997, 336, 233.