Simple Tetrahydroisoquinolines Are Potent and Selective Kappa Opioid Receptor Antagonists

Article abstract of DOI:10.1021/acsmedchemlett.7b00115

Potent and selective κ opioid receptor antagonists have been derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid receptor antagonists. In order to determine if the 3-hydroxyphenyl and/or the piperidine amino groups are required for obtaining the pure opioid antagonists, (3R)-7-hydroxy-N-[(1S)-2-methyl-1-(piperidine-1-ylmethyl)propyl]-1,2,3,4-tetrahydroiosquinoline-3-carboxamide (1), which does not have a 4-(3-hydroxyphenyl) group, and (3R)-N-(1R)-1-(cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2), which does not have a 4-hydroxylphenyl or a piperidine amino group, were synthesized and evaluated for their [³⁵S]GTPγS binding properties at the μ, δ, and κ opioid receptors. Surprisingly compound 1 remained a pure opioid antagonist with a K_e = 6.80 nM at the κ opioid receptor and is 21- and 441-fold selective for the κ receptor relative to the μ and δ opioid receptors, respectively. Even more unexpected and novel is the finding that 2 has a K_e = 0.14 nM at κ and is 1730- and 4570-fold selective for κ relative to the μ and δ opioid receptors, respectively.

Full text of DOI:10.1021/acsmedchemlett.7b00115

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Letter
Simple Tetrahydroisoquinolines are Potent and
Selective Kappa Opioid Receptor Antagonists
Chad M. Kormos, Pauline W. Ondachi, Scott P Runyon, James B. Thomas, Samuel
Wayne Mascarella, Ann M. Decker, Hernán A Navarro, and F. Ivy Ivy Carroll
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 25 May 2017
Downloaded from http://pubs.acs.org on May 26, 2017
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Simple Tetrahydroisoquinolines are Potent and Selective Kappa
Opioid Receptor Antagonists
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Chad M. Kormos, Pauline W. Ondachi, Scott P. Runyon, James B. Thomas, S. Wayne Mascarella, Ann
M. Decker, Hernán A. Navarro, and F. Ivy Carroll*
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709ꢀ2194, United States
opioid receptor, kappa opioid receptor antagonists, functional assays, tetrahydroisoquinoline, JDTic
ABSTRACT: Potent and selective κ opioid receptor antagonists have been derived from the Nꢀsubstituted transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀ
hydroxyphenyl)piperidine class of pure opioid receptor antagonists. In order to determine if the 3ꢀhydroxyphenyl and/or the piperiꢀ
dine amino groups are required for obtaining the pure opioid antagonists, (3R)ꢀ7ꢀHydroxyꢀNꢀ[(1S)ꢀ2ꢀmethylꢀ1ꢀ(piperidineꢀ1ꢀ
ylmethyl)propyl]ꢀ1,2,3,4ꢀtetrahydroiosquinolineꢀ3ꢀcarboxamide (1), which does not have a 4ꢀ(3ꢀhydroxyphenyl) group and (3R)ꢀNꢀ
(1R)ꢀ1ꢀ(cyclohexylmethyl)ꢀ2ꢀmethylpropyl]ꢀ7ꢀhydroxyꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ3ꢀcarboxamide (2), which does not have a
(4ꢀhydroxylphenyl) or a piperidine amino group were synthesized and evaluated for their [35S]GTPγS binding properties at the ꢁ, δ,
and κ opioid receptors. Surprisingly compound 1 remained a pure opioid antagonist with a Ke = 6.80 nM at the κ opioid receptor
and is 21ꢀ and 441ꢀfold selective for the κ receptor relative to the ꢁ and δ opioid receptors, respectively. Even more unexpected and
novel is the finding that 2 has a Ke = 0.14 nM at the κ and is 1730ꢀ and 4570ꢀfold selective for the κ relative to the ꢁ and δ opioid
receptors, respectively.
In previous reports we found that JDTic [(3R)ꢀ1,2,3,4ꢀ
OH
OH
tetrahydroꢀ7ꢀhydroxyꢀΝꢀ[(1S)ꢀ1ꢀ[[(3R,4R)ꢀ4ꢀ(3ꢀ
hydroxyphenyl)ꢀ3,4ꢀdimethylꢀ1ꢀpiperidinyl]methyl]ꢀ2ꢀ
HO
HO
N
O
HO
HO
N
N
N
NH2
NH
NH
methylpropyl]ꢀ3ꢀisoquinolinecarboxamide] was a potent and
selective κ opioid receptor antagonist1,2 using in vitro assays
and animal studies.3 In addition we reported that JDTic deꢀ
creased immobility and increased swimming in the forced
swim antidepressant test,4 and showed anxiolyticꢀlike effects
in the elevated plus maze and fearꢀpotentiated startle test5,
suggesting that JDTic may be effective for treating coꢀmorbid
depression and anxiety disorders. We also showed that JDTic
prevented resumption of cocaine seeking precipitated by a
stressor (an animal relapse model),4 was active in the ethanol
Pavlovian spontaneous recovery test (a rat model of alcohol
seeking)6 and ethanol deprivation test (an alcohol relapse
model),6 and blocked the expression of nicotine withdrawal
signs.7 All of the behavioral effects associated with blocking κ
opioid receptor activity lend support to the notion that κ opioid
receptor antagonists may be useful as treatments for depresꢀ
sion, schizophrenia, anxiety, and substance abuse addiction.
N
N
H
O
H
O
2
NH
O
1
NH
N
F
N
H
H
LY2456302
O
O
JDTic
10
Figure 1. Structures of JDTic, tetrahydroisoquinoline compounds
1, 2, compound 10, and LY2456302.
Compound 1 was synthesized as shown in Scheme 1. Comꢀ
pound 4 was synthesized by coupling piperidine (3)with Nꢀ
BocꢀLꢀvaline followed by treatment with hydrochloric acid in
methanol to remove the tertꢀbutyloxycarbonyl protecting
group. Reduction of 4 with borane yielded 5. Coupling of 5
with Bocꢀ7ꢀhydroxyꢀDꢀTicꢀOH using EDC•HCl and triethylꢀ
amine in dichloromethane followed by treatment with hydroꢀ
chloric acid in methanol yielded 1.
Scheme 1a
As a continuation of our efforts to develop potent and selecꢀ
tive κ opioid receptor antagonists as potential pharmacotheraꢀ
pies for treating CNS disorders, the relatively simple (3R)ꢀ
1,2,3,4ꢀtetrahydroꢀ7ꢀhydroxyꢀ3ꢀisoquinolinecaboxamides
1
and 2 were designed, synthesized, and evaluated in vitro using
a [35S]GTPγS binding assay at the κ, ꢁ, and δ opioid receptors.
In addition, compounds 1 and 2 were docked to the hKOR
crystal structure and the specific binding interaction of 1 and 2
compared to that of JDTic.
aReagents and conditions: a) NꢀBocꢀLꢀValine, HBTU, CH3CN,
rt, overnight; b) HCl, CH3OH; c) BH3, THF, reflux, 3 h; d) Bocꢀ7ꢀ
hydroxyꢀDꢀTic(OH), EDC•HCl, HOBt, NEt3, CH2Cl2, rt, overꢀ
night.
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Compound 2 was prepared according to the sequence shown dimethylphenyl)pyrrolidinꢀ1ꢀyl)methyl)phenoxy)ꢀ3ꢀ
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fluorobenzamide (Figure 1),9 the only κ opioid receptor antagꢀ
onist still in clinical development, shows that 2 is 5.8 times
more potent as a κ opioid antagonist than LY2456302. Since
LY2456302 has ꢁ/κ and δ/κ values of 21 and 136, respectiveꢀ
ly, compound 2 is a much more selective κ opioid receptor
antagonist in the [35S]GTPγS binding assay.
1
2
3
4
5
6
7
8
in Scheme 2. The aldehyde 6 was condensed with (R)ꢀtertꢀ
butylsulfinamide in the presence of pyridinium tosylate and
magnesium sulfate to give 7. The resulting sulfinimine 7 was
condensed with isopropyl Grignard reagent in dichloroꢀ
methane to afford a high diastereomeric excess of the tertꢀ
butylsulfinamide 8. Treatment of 8 with hydrogen chloride in
dioxane and methanol yielded the amine 9. Coupling of 9 with
Bocꢀ7ꢀhydroxyꢀDꢀTic(OH) using DCC in the presence of
HOBt and triethylamine in tetrahydrofuran followed by treatꢀ
ment with 6N hydrochloric acid in aqueous methanol afforded
2.
Table 2 shows a comparison of the calculated physiochemiꢀ
cal properties of 2 to those of JDTic and LY2456302. Studies
by others have shown that compounds can be expected to be
CNSꢀpenetrant if their calculated topological polar surface
area (TPSA) values are less than 76 Å2,10 and clogP values
range from 2 ꢀ 411. Compound 2 has a TPSA value of 61.36Å2
compared to 84.83 for JDTic and 55.56 Å2 for LY2456302,
and a clogP value of 4 compared to 3.6 for JDTic and 5.63 for
LY2456302. Using these calculated polarity and lipophilicity
values a logBB value of ꢀ0.16 can be calculated for compound
2, which reinforces the prediction it can be expected to peneꢀ
trate into the CNS.11 Using another measure of CNS drugꢀ
likeness, the CNS MPO (Multi Parameter Optimization),
Wagner, et al. found that 74% of CNS drugs surveyed were
calculated to have a CNS MPO value greater than or equal to
four.12 Compound 2 has a CNS MPO score of 3.7 compared to
3.1 and 2.9 for JDTic and LY2456302, respectively. In a reꢀ
cent review of methods used for predicting drug CNS penetraꢀ
tion, Pike found CNS penetration correlated with lower moꢀ
lecular weight.13 With a molecular weight of 344.5 Daltons
compound 2 has a molecular weight of 121.1 and 74 Daltons
less than the molecular weights of JDTic and LY2456302,
respectively.
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Scheme 2a
aReagents and conditions: a) (R)ꢀtertꢀButylsulfinamide,
MgSO4, pyridinium tosylate, CH2Cl2, rt, overnight; b) iPrMgCl,
CH2Cl2; c) HCl in 1,4ꢀdioxane, CH3OH, rt, 3 h; d) i. Bocꢀ7ꢀ
hydroxyꢀDꢀTic(OH), DCC, HOBt, NEt3, THF, rt, overnight; ii.
6N HCl aq., CH3OH.
In a recent study we reported that the JDTic analog 10 (Figꢀ
ure 1), where both the 3ꢀ and 4ꢀmethyl groups were removed
was still a pure opioid receptor antagonist.8 In the present
study compound 1 was synthesized and evaluated for opioid
receptor antagonist activity using [35S]GTPγS binding assays
in order to determine the effect of removing the 3ꢀ
hydroxyphenyl group from 10 (Table 1). The assay measures
the ability of an antagonist to inhibit agonistꢀstimulated
[35S]GTPγS binding. Concentration response curves of
U69,593 (κ), DAMGO (ꢁ), or DPDPE (δ) were run in the abꢀ
sence and presence of a single concentration of test compound.
Ke values were calculated with the equation Ke = [L]/(ER – 1)
where [L] is the concentration of test compound and ER is the
ratio of EC50 values in the presence and absence of test comꢀ
pound. Ke values were considered valid when the ER was at
least 4. Compound 1, like JDTic and 10, was found to be a
pure opioid receptor antagonist (no agonist activity at 10 ꢁM).
However, with a Ke value of 6.8 nM at the κ opioid receptor, 1
was less potent than 10 as a κ antagonist. In addition, with ꢁ/κ
and δ/κ values of 21 and >400, respectively, 1 was less selecꢀ
tive at κ relative to the ꢁ and δ receptors than JDTic and 10.
Nevertheless, its pure opioid antagonist properties were highly
interesting and led us to design and synthesize compound 2,
which has a carbon replacing the piperidine nitrogen in 1.
Compound 2 was a pure opioid receptor antagonist and has a
Ke = 0.14 nM at the κ opioid receptor and thus, has essentially
the same potency as 10 as a κ opioid receptor antagonist.
Moreover, with Ke values of 242 and 640 nM at the ꢁ and δ
receptors, respectively, compound 2 is highly selective for the
κ relative to the ꢁ and δ opioid receptors.
In order to assess the possibility of contrasting ligandꢀ
receptor binding interactions or poses resulting from the strucꢀ
tural differences between compounds 1 and 2 (in comparison
with JDTic) a series of docking studies were performed. These
calculations were intended to determine whether it could be
anticipated that the pharmacology of compounds 1 and 2 could
differ from one another or from JDTic. The docking calculaꢀ
tions were performed using the known Xꢀray crystallographic
structure of the kappa opioid receptor in complex with
JDTic.14,15 An overlay of the calculated binding poses of comꢀ
pounds 1 and 2, and the experimental binding pose of JDTic is
illustrated in Figure 2. Receptor residueꢀligand interactions are
summarized in the twoꢀdimensional interaction diagrams (Figꢀ
ure S1, B, and C).16 As can be seen in these figures, all three
compounds share the critical opioid receptor interaction with
ASP138. The tetrahydroquinoline ring system of all three are
closely aligned and reside in the pocket defined by ILE290,
PHE 231, ILE294, LYS227, and TYR139. This is depicted in
the docking calculation and also predicts that the tetrahydroꢀ
quinoline hydroxy of compounds 1 and 2 participates in a hyꢀ
drogen bond with a receptor site water molecule as observed
in the JDTic Xꢀray structure. Besides these interactions of the
tetrahydroquinoline ring and substituent, the predicted binding
pose of compound 2 is otherwise quite similar to that observed
for JDTic. The compound 2 and JDTic isopropyl groups overꢀ
lap closely and reside in the pocket defined by TRP287,
TYR320, and ILE316. Likewise, there is a close overlay of the
analogous compound 2 cyclohexyl and JDTic piperidine rings.
In contrast, the predicted binding pose of compound 1 divergꢀ
es from that of both compound 1 and JDTic in that the relative
positions of the isopropyl group and the terminal sixꢀ
A comparison of the κ, ꢁ, and δ Ke values of 2 to those of
JDTic shows that 2 is only 7 times less potent as a κ antagonist
than JDTic and is a slightly more selective κ antagonist than
JDTic (Table 1). A comparison of the κ, ꢁ, and δ Ke values of
2
to
those
of
LY2456302,
(S)ꢀ4ꢀ(4ꢀ((2ꢀ(3,5ꢀ
2
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membered ring are exchanged. In addition, this calculated
conformational change suggests the possibility of new binding
1
2
3
4
5
6
7
8
In summary, we found that 1, which has only a simple piꢀ
peridine ring where JDTic has a structurally complex transꢀ
3,4ꢀdimethylꢀ4ꢀ(3ꢀhydroxyphenyl)piperidine group was still a
pure opioid receptor antagonist and has a Ke = 6.80 nM at the
κ opioid receptor and is 21ꢀ and >441ꢀfold selective for the κ
receptor relative to the ꢁ and δ opioid receptors, respectively.
Even more unexpected and novel is the finding that 2 which
does not have the piperidine amino group that is present in 1
has a Ke = 0.14 nM at the κ and is 1730ꢀ and 4570ꢀfold selecꢀ
tive for the KOR relative to the ꢁ and δ opioid receptors, reꢀ
spectively. Docking studies of compounds 1 and 2 to the
hKOR crystal structure of JDTic revealed differences and simꢀ
ilarities of the binding interaction of 1 and 2 to each other as
well as to JDTic.
interactions for compound 2. A possible cationꢀaromatic π
interaction may exist between TYR320 and the protonated
compound 2 piperidine nitrogen. In addition, the piperidine
nitrogen is predicted to be in range for polar interactions with
ASP138 and a receptor site water. The compound 2 docking
study suggests that, although the compound 2 structure shares
more features in common (relative to compound 1) with the
parent JDTic structure, compound 2 has access to alternative
binding modes not observed for JDTic.
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On the basis of these highly interesting properties of 1 and 2
we plan to further develop these two lead structures to identify
compounds that have even better κ opioid receptor potency
and selectivity as well as drug like properties. Such comꢀ
pounds will then be evaluated in behavioral assays used for the
development of JDTic with the hope that one or more of the
compounds will have suitable properties for clinical developꢀ
ment.
Figure 2. Overlay of the observed binding pose of JDTic (red)
and the calculated binding poses of compounds 1 (green) and 2
(blue) in the kappa opioid receptor (PDB 4DJH). Binding pocket
residue sideꢀchains (gray) and waters (dark blue) are also illustratꢀ
ed. Hydrogen bonds are show as yellow dashedꢀlines.
Table 1. Comparison of the Inhibition of AgonistꢀStimulated [35S]GTPγS Binding in Cloned Human ꢁ, δ, and κ Opioid Reꢀ
ceptors for Compounds 1 and 2 to those of JDTic, LY2456302a
Ke (nM)a
ꢁ, DAMGO
25 ± 4
δ, DPDPE
74 ± 2
κ, U69,593
0.02 ± 0.01
6.8 ± 2.1
ꢁ/κ
1250
21
δ/κ
JDTic
3700
>440
4570
2400
136
1
144 ± 37
242 ± 36
12.3 ± 1.0
17.4
>3000
2
640 ± 170
240 ± 73
110
0.14 ± 0.03
0.10 ± 0.03
0.81
1730
123
21
10
LY2456302b
aKe values are the mean ± SEM of at least three independent experiments performed in duplicate. Neither 1 nor 2 had any agonist activiꢀ
ty at 10 ꢁM. bKe values from Ref 9 are reported for this compound.
Table 2. Comparison of the Calculated Physiochemical Properties of 2 to those of JDTic and LY2456302
TPSA
84.83
61.36
55.56
clogP
3.60
4.0
logBB
ꢀ0.57
ꢀ0.16
0.17
CNS MPO
MW
465.6
344.5
418.5
JDTic
2
3.1
3.7
2.9
LY2456302
5.63
chemical properties is given. This information is available free of
charge via the Internet at http://pubs.acs.org.
ASSOCIATED CONTENT
Supporting Information
AUTHOR INFORMATION
Experimental procedures for the synthesis of 1 and 2, analytical
data, [35S]GTPγS binding methods and calculation of physioꢀ
Corresponding Author
*F. Ivy Carroll, Ph.D.
3
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stressors vs cocaine primes and its antidepressantꢀlike effects in rats.
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(5) Knoll, A. T.; Meloni, E. G.; Thomas, J. B.; Carroll, F. I.;
Carlezon, W. A., Jr. Anxiolyticꢀlike effects of κꢀopioid receptor
antagonists in models of unlearned and learned fear in rats. J.
Pharmacol. Exp. Ther. 2007, 323, 838ꢀ845.
Research Triangle Institute
Post Office Box 12194
Research Triangle Park, NC 27709ꢀ2194
Telephone: 919 541ꢀ6679
Fax: 919 541ꢀ8868
1
2
3
4
Email: fic@rti.org
5
(6)
Deehan Jr, G. A.; McKinzie, D. L.; Carroll, F. I.; McBride,
W. J.; Rodd, Z. A. The longꢀlasting effects of JDTic, a kappa opioid
receptor antagonist, on the expression of ethanolꢀseeking behavior
and the relapse drinking of female alcoholꢀpreferring (P) rats.
Pharmacol. Biochem. Behav. 2012, 101, 581ꢀ587.
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Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
(7)
Jackson, K. J.; Carroll, F. I.; Negus, S. S.; Damaj, M. I.
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Funding Sources
This research was supported by the National Institute on Drug
Abuse Grant DA12001).
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Carroll, F. I.; Gichinga, M. G.; Kormos, C. M.; Maitra, R.;
Runyon, S. P.; Thomas, J. B.; Mascarella, S. W.; Decker, A. M.;
Navarro, H. A. Design, synthesis, and pharmacological evaluation of
JDTic analogs to examine the significance of the 3ꢀ and 4ꢀmethyl
substituents. Bioorg. Med. Chem. 2015, 23, 6379ꢀ88.
ACKNOWLEDGMENT
We thank Keith Warner and Tiffany Langston for conducting the
in vitro testing.
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E. L.; McKinzie, J. H.; Kahl, S. D.; Forster, B. M.; Wong, C. J.; Li,
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ABBREVIATIONS
[35S]GTPγS,
sulfurꢀ35
guanosineꢀ5´ꢀOꢀ(3ꢀthio)triphosphate;
DAMGO, [DꢀAla2,MePhe4,Glyꢀol5]enkephalin; DPDPE, [Dꢀ
Pen2,DꢀPen5]enkephalin; U69,593, (5α,7α,8β)ꢀ(–)ꢀNꢀmethylꢀNꢀ
[7ꢀ(1ꢀpyrrolidinyl)ꢀ1ꢀoxaspiroꢀ[4.5]decꢀ8ꢀyl]benzeneacetamide;
EDC, 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide; DCC,
N,N´ꢀdicyclohexylcarbodiimide; HOBt, hydroxybenzotriazole
Notes
The authors declare no competing financial interest.
REFERENCES
(1)
Thomas, J. B.; Atkinson, R. N.; Vinson, N. A.; Catanzaro,
J. L.; Perretta, C. L.; Fix, S. E.; Mascarella, S. W.; Rothman, R. B.;
Xu, H.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F.
I. Identification of (3R)ꢀ7ꢀhydroxyꢀNꢀ((1S)ꢀ1ꢀ[[(3R,4R)ꢀ4ꢀ(3ꢀ
hydroxyphenyl)ꢀ3,4ꢀdimethylꢀ1ꢀpiperidinyl]methyl]ꢀ2ꢀmethylpropyl)ꢀ
1,2,3,4ꢀtetrahydroꢀ3ꢀisoquinolinecarboxamide as a novel potent and
selective opioid kappa receptor antagonist. J. Med. Chem. 2003, 46,
3127ꢀ3137.
(2)
Thomas, J. B.; Atkinson, R. N.; Rothman, R. B.; Fix, S. E.;
Mascarella, S. W.; Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y.;
Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification of the
first
transꢀ(3R,4R)ꢀdimethylꢀ4ꢀ(3ꢀhydroxyphenyl)piperidine
derivative to possess highly potent and selective opioid kappa
receptor antagonist activity. J. Med. Chem. 2001, 44, 2687ꢀ90.
(3)
Carroll, F. I.; Thomas, J. B.; Dykstra, L. A.; Granger, A.
L.; Allen, R. M.; Howard, J. L.; Pollard, G. T.; Aceto, M. D.; Harris,
L. S. Pharmacological properties of JDTic: a novel kappaꢀopioid
receptor antagonist. Eur. J. Pharmacol. 2004, 501, 111ꢀ119.
(4)
Beardsley, P. M.; Howard, J. L.; Shelton, K. L.; Carroll, F.
I. Differential effects of the novel kappa opioid receptor antagonist,
JDTic, on reinstatement of cocaineꢀseeking induced by footshock
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Scheme 1
119x38mm (289 x 289 DPI)
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Scheme 2
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Figure 2
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Graphical Abstract
564x564mm (72 x 72 DPI)
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