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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
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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ACS Medicinal Chemistry Letters
Simple Tetrahydroisoquinolines are Potent and Selective Kappa Opioid Receptor Antagonists 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 27709-2194, 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 N-substituted trans-3,4-dimethyl-4-(3hydroxyphenyl)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-1ylmethyl)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 Ke = 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 Ke = 0.14 nM at the κ and is 1730- and 4570-fold selective for the κ relative to the µ and δ opioid
receptors, respectively.
In previous reports we found that JDTic [(3R)-1,2,3,4tetrahydro-7-hydroxy-Ν-[(1S)-1-[[(3R,4R)-4-(3hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2methylpropyl]-3-isoquinolinecarboxamide] was a potent and selective κ opioid receptor antagonist1,2 using in vitro assays and animal studies.3 In addition we reported that JDTic decreased immobility and increased swimming in the forced swim antidepressant test,4 and showed anxiolytic-like effects in the elevated plus maze and fear-potentiated startle test5, suggesting that JDTic may be effective for treating co-morbid 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 depression, schizophrenia, anxiety, and substance abuse addiction. As a continuation of our efforts to develop potent and selective κ opioid receptor antagonists as potential pharmacotherapies for treating CNS disorders, the relatively simple (3R)1,2,3,4-tetrahydro-7-hydroxy-3-isoquinolinecaboxamides 1 and 2 were designed, synthesized, and evaluated in vitro using a [35S]GTPγS binding assay at the κ, µ, 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.
OH
OH
HO
HO HO
N
O HO
N
N H
NH
N H
O JDTic
NH O 1
N H
N
N
NH
2
NH2 O
O N H
NH O
F LY2456302
10
Figure 1. Structures of JDTic, tetrahydroisoquinoline compounds 1, 2, compound 10, and LY2456302.
Compound 1 was synthesized as shown in Scheme 1. Compound 4 was synthesized by coupling piperidine (3)with NBoc-L-valine followed by treatment with hydrochloric acid in methanol to remove the tert-butyloxycarbonyl protecting group. Reduction of 4 with borane yielded 5. Coupling of 5 with Boc-7-hydroxy-D-Tic-OH using EDC•HCl and triethylamine in dichloromethane followed by treatment with hydrochloric acid in methanol yielded 1. Scheme 1a
a
Reagents and conditions: a) N-Boc-L-Valine, HBTU, CH3CN, rt, overnight; b) HCl, CH3OH; c) BH3, THF, reflux, 3 h; d) Boc-7hydroxy-D-Tic(OH), EDC•HCl, HOBt, NEt3, CH2Cl2, rt, overnight.
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Compound 2 was prepared according to the sequence shown in Scheme 2. The aldehyde 6 was condensed with (R)-tertbutylsulfinamide in the presence of pyridinium tosylate and magnesium sulfate to give 7. The resulting sulfinimine 7 was condensed with isopropyl Grignard reagent in dichloromethane to afford a high diastereomeric excess of the tertbutylsulfinamide 8. Treatment of 8 with hydrogen chloride in dioxane and methanol yielded the amine 9. Coupling of 9 with Boc-7-hydroxy-D-Tic(OH) using DCC in the presence of HOBt and triethylamine in tetrahydrofuran followed by treatment with 6N hydrochloric acid in aqueous methanol afforded 2. Scheme 2a
a Reagents and conditions: a) (R)-tert-Butylsulfinamide, MgSO4, pyridinium tosylate, CH2Cl2, rt, overnight; b) iPrMgCl, CH2Cl2; c) HCl in 1,4-dioxane, CH3OH, rt, 3 h; d) i. Boc-7hydroxy-D-Tic(OH), DCC, HOBt, NEt3, THF, rt, overnight; ii. 6N HCl aq., CH3OH.
In a recent study we reported that the JDTic analog 10 (Figure 1), where both the 3- and 4-methyl 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 3hydroxyphenyl group from 10 (Table 1). The assay measures the ability of an antagonist to inhibit agonist-stimulated [35S]GTPγS binding. Concentration response curves of U69,593 (κ), DAMGO (µ), or DPDPE (δ) were run in the absence 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 compound. 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 µM). 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 µ/κ and δ/κ values of 21 and >400, respectively, 1 was less selective at κ relative to the µ 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 µ and δ receptors, respectively, compound 2 is highly selective for the κ relative to the µ and δ opioid receptors. A comparison of the κ, µ, 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, µ, and δ Ke values of 2 to those of LY2456302, (S)-4-(4-((2-(3,5-
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dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)-3fluorobenzamide (Figure 1),9 the only κ opioid receptor antagonist still in clinical development, shows that 2 is 5.8 times more potent as a κ opioid antagonist than LY2456302. Since LY2456302 has µ/κ and δ/κ values of 21 and 136, respectively, compound 2 is a much more selective κ opioid receptor antagonist in the [35S]GTPγS binding assay. Table 2 shows a comparison of the calculated physiochemical properties of 2 to those of JDTic and LY2456302. Studies by others have shown that compounds can be expected to be CNS-penetrant 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 penetrate into the CNS.11 Using another measure of CNS druglikeness, 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 recent review of methods used for predicting drug CNS penetration, Pike found CNS penetration correlated with lower molecular 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. In order to assess the possibility of contrasting ligandreceptor binding interactions or poses resulting from the structural 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 calculations were performed using the known X-ray crystallographic structure of the kappa opioid receptor in complex with JDTic.14,15 An overlay of the calculated binding poses of compounds 1 and 2, and the experimental binding pose of JDTic is illustrated in Figure 2. Receptor residue-ligand interactions are summarized in the two-dimensional interaction diagrams (Figure 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 tetrahydroquinoline hydroxy of compounds 1 and 2 participates in a hydrogen bond with a receptor site water molecule as observed in the JDTic X-ray 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 overlap 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 diverges from that of both compound 1 and JDTic in that the relative positions of the isopropyl group and the terminal six-
2
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membered ring are exchanged. In addition, this calculated conformational change suggests the possibility of new binding interactions for compound 2. A possible cation-aromatic 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.
In summary, we found that 1, which has only a simple piperidine ring where JDTic has a structurally complex trans3,4-dimethyl-4-(3-hydroxyphenyl)piperidine group was still a pure opioid receptor antagonist and has a Ke = 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 which does not have the piperidine amino group that is present in 1 has a Ke = 0.14 nM at the κ and is 1730- and 4570-fold selective for the KOR relative to the µ and δ opioid receptors, respectively. Docking studies of compounds 1 and 2 to the hKOR crystal structure of JDTic revealed differences and similarities of the binding interaction of 1 and 2 to each other as well as to JDTic. 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 compounds 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 development.
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 side-chains (gray) and waters (dark blue) are also illustrated. Hydrogen bonds are show as yellow dashed-lines.
Table 1. Comparison of the Inhibition of Agonist-Stimulated [35S]GTPγS Binding in Cloned Human µ, δ, and κ Opioid Receptors for Compounds 1 and 2 to those of JDTic, LY2456302a Ke (nM)a µ, DAMGO
δ, DPDPE
κ, U69,593
µ/κ
δ/κ
JDTic
25 ± 4
74 ± 2
0.02 ± 0.01
1250
3700
1
144 ± 37
>3000
6.8 ± 2.1
21
>440
2
242 ± 36
640 ± 170
0.14 ± 0.03
1730
4570
12.3 ± 1.0
240 ± 73
0.10 ± 0.03
123
2400
17.4
110
0.81
21
136
10 LY2456302
b
a
Ke values are the mean ± SEM of at least three independent experiments performed in duplicate. Neither 1 nor 2 had any agonist activity at 10 µM. 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
JDTic
TPSA
clogP
logBB
CNS MPO
MW
84.83
3.60
-0.57
3.1
465.6
2
61.36
4.0
-0.16
3.7
344.5
LY2456302
55.56
5.63
0.17
2.9
418.5
chemical properties is given. This information is available free of charge via the Internet at http://pubs.acs.org.
ASSOCIATED CONTENT Supporting Information Experimental procedures for the synthesis of 1 and 2, analytical data, [35S]GTPγS binding methods and calculation of physio-
AUTHOR INFORMATION Corresponding Author *F. Ivy Carroll, Ph.D.
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Research Triangle Institute Post Office Box 12194 Research Triangle Park, NC 27709-2194 Telephone: 919 541-6679 Fax: 919 541-8868 Email: [email protected]
Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Funding Sources This research was supported by the National Institute on Drug Abuse Grant DA12001).
ACKNOWLEDGMENT We thank Keith Warner and Tiffany Langston for conducting the in vitro testing.
ABBREVIATIONS [35S]GTPγS, sulfur-35 guanosine-5´-O-(3-thio)triphosphate; DAMGO, [D-Ala2,MePhe4,Gly-ol5]enkephalin; DPDPE, [DPen2,D-Pen5]enkephalin; U69,593, (5α,7α,8β)-(–)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro-[4.5]dec-8-yl]benzeneacetamide; EDC, 1-ethyl-3-(3-dimethylaminopropyl)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)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)1,2,3,4-tetrahydro-3-isoquinolinecarboxamide as a novel potent and selective opioid kappa receptor antagonist. J. Med. Chem. 2003, 46, 3127-3137. (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 trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity. J. Med. Chem. 2001, 44, 2687-90. (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 kappa-opioid receptor antagonist. Eur. J. Pharmacol. 2004, 501, 111-119. (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 cocaine-seeking induced by footshock
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stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl.) 2005, 183, 118-126. (5) Knoll, A. T.; Meloni, E. G.; Thomas, J. B.; Carroll, F. I.; Carlezon, W. A., Jr. Anxiolytic-like effects of κ-opioid receptor antagonists in models of unlearned and learned fear in rats. J. Pharmacol. Exp. Ther. 2007, 323, 838-845. (6) Deehan Jr, G. A.; McKinzie, D. L.; Carroll, F. I.; McBride, W. J.; Rodd, Z. A. The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats. Pharmacol. Biochem. Behav. 2012, 101, 581-587. (7) Jackson, K. J.; Carroll, F. I.; Negus, S. S.; Damaj, M. I. Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse. Psychopharmacology (Berl.) 2010, 210, 285-294. (8) 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 3- and 4-methyl substituents. Bioorg. Med. Chem. 2015, 23, 6379-88. (9) Rorick-Kehn, L. M.; Witkin, J. M.; Statnick, M. A.; Eberle, E. L.; McKinzie, J. H.; Kahl, S. D.; Forster, B. M.; Wong, C. J.; Li, X.; Crile, R. S.; Shaw, D. B.; Sahr, A. E.; Adams, B. L.; Quimby, S. J.; Diaz, N.; Jimenez, A.; Pedregal, C.; Mitch, C. H.; Knopp, K. L.; Anderson, W. H.; Cramer, J. W.; McKinzie, D. L. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology 2014, 77, 131144. (10) Summerfeld, S. G.; Read, K.; Begley, D. J.; Obradovic, T.; Hidalgo, I. J.; Coggon, S.; Lewis, A. V.; Porter, R. A.; Jeffrey, P. Central nervous system drug disposition: The relationship between in situ brain permeability and brain free fraction. J. Pharmacol. Exp. Ther. 2007, 322, 205-213. (11) Ghose, A. K.; Herbertz, T.; Hudkins, R. L.; Dorsey, B. D.; Mallamo, J. P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 2012, 3, 50-68. (12) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 2010, 1, 43549. (13) Pike, V. W. Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging. Curr. Med. Chem. 2016, 23, 1818-69. (14) PDB: 4DJH, Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X. P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human kappa-opioid receptor in complex with JDTic. Nature 2012, 485, 32732. (15) Surflex-Dock version 2.7, Jain, A. N. Surflex: fully automatic flexible molecular docking using a molecular similaritybased search engine. J Med Chem 2003, 46, 499-511. (16) Schrödinger Release 2017-1: Maestro, Schrödinger, LLC, New York, NY, 2017. In.
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OH
OH
HO HO
HO
N
N
N H
O
HO
NH O
N H
NH O 1
N H
N
NH O 2
N H
JDTic
NH O 10
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N
NH2 O F LY2456302
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Scheme 1 119x38mm (289 x 289 DPI)
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Scheme 2 156x39mm (288 x 289 DPI)
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Figure 2 716x761mm (72 x 72 DPI)
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Graphical Abstract 564x564mm (72 x 72 DPI)
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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
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Simple Tetrahydroisoquinolines are Potent and Selective Kappa Opioid Receptor Antagonists 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 27709-2194, 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 N-substituted trans-3,4-dimethyl-4-(3hydroxyphenyl)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-1ylmethyl)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 Ke = 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 Ke = 0.14 nM at the κ and is 1730- and 4570-fold selective for the κ relative to the µ and δ opioid
receptors, respectively.
In previous reports we found that JDTic [(3R)-1,2,3,4tetrahydro-7-hydroxy-Ν-[(1S)-1-[[(3R,4R)-4-(3hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2methylpropyl]-3-isoquinolinecarboxamide] was a potent and selective κ opioid receptor antagonist1,2 using in vitro assays and animal studies.3 In addition we reported that JDTic decreased immobility and increased swimming in the forced swim antidepressant test,4 and showed anxiolytic-like effects in the elevated plus maze and fear-potentiated startle test5, suggesting that JDTic may be effective for treating co-morbid 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 depression, schizophrenia, anxiety, and substance abuse addiction. As a continuation of our efforts to develop potent and selective κ opioid receptor antagonists as potential pharmacotherapies for treating CNS disorders, the relatively simple (3R)1,2,3,4-tetrahydro-7-hydroxy-3-isoquinolinecaboxamides 1 and 2 were designed, synthesized, and evaluated in vitro using a [35S]GTPγS binding assay at the κ, µ, 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.
OH
OH
HO
HO HO
N
O HO
N
N H
NH
N H
O JDTic
NH O 1
N H
N
N
NH
2
NH2 O
O N H
NH O
F LY2456302
10
Figure 1. Structures of JDTic, tetrahydroisoquinoline compounds 1, 2, compound 10, and LY2456302.
Compound 1 was synthesized as shown in Scheme 1. Compound 4 was synthesized by coupling piperidine (3)with NBoc-L-valine followed by treatment with hydrochloric acid in methanol to remove the tert-butyloxycarbonyl protecting group. Reduction of 4 with borane yielded 5. Coupling of 5 with Boc-7-hydroxy-D-Tic-OH using EDC•HCl and triethylamine in dichloromethane followed by treatment with hydrochloric acid in methanol yielded 1. Scheme 1a
a
Reagents and conditions: a) N-Boc-L-Valine, HBTU, CH3CN, rt, overnight; b) HCl, CH3OH; c) BH3, THF, reflux, 3 h; d) Boc-7hydroxy-D-Tic(OH), EDC•HCl, HOBt, NEt3, CH2Cl2, rt, overnight.
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Compound 2 was prepared according to the sequence shown in Scheme 2. The aldehyde 6 was condensed with (R)-tertbutylsulfinamide in the presence of pyridinium tosylate and magnesium sulfate to give 7. The resulting sulfinimine 7 was condensed with isopropyl Grignard reagent in dichloromethane to afford a high diastereomeric excess of the tertbutylsulfinamide 8. Treatment of 8 with hydrogen chloride in dioxane and methanol yielded the amine 9. Coupling of 9 with Boc-7-hydroxy-D-Tic(OH) using DCC in the presence of HOBt and triethylamine in tetrahydrofuran followed by treatment with 6N hydrochloric acid in aqueous methanol afforded 2. Scheme 2a
a Reagents and conditions: a) (R)-tert-Butylsulfinamide, MgSO4, pyridinium tosylate, CH2Cl2, rt, overnight; b) iPrMgCl, CH2Cl2; c) HCl in 1,4-dioxane, CH3OH, rt, 3 h; d) i. Boc-7hydroxy-D-Tic(OH), DCC, HOBt, NEt3, THF, rt, overnight; ii. 6N HCl aq., CH3OH.
In a recent study we reported that the JDTic analog 10 (Figure 1), where both the 3- and 4-methyl 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 3hydroxyphenyl group from 10 (Table 1). The assay measures the ability of an antagonist to inhibit agonist-stimulated [35S]GTPγS binding. Concentration response curves of U69,593 (κ), DAMGO (µ), or DPDPE (δ) were run in the absence 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 compound. 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 µM). 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 µ/κ and δ/κ values of 21 and >400, respectively, 1 was less selective at κ relative to the µ 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 µ and δ receptors, respectively, compound 2 is highly selective for the κ relative to the µ and δ opioid receptors. A comparison of the κ, µ, 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, µ, and δ Ke values of 2 to those of LY2456302, (S)-4-(4-((2-(3,5-
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dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)-3fluorobenzamide (Figure 1),9 the only κ opioid receptor antagonist still in clinical development, shows that 2 is 5.8 times more potent as a κ opioid antagonist than LY2456302. Since LY2456302 has µ/κ and δ/κ values of 21 and 136, respectively, compound 2 is a much more selective κ opioid receptor antagonist in the [35S]GTPγS binding assay. Table 2 shows a comparison of the calculated physiochemical properties of 2 to those of JDTic and LY2456302. Studies by others have shown that compounds can be expected to be CNS-penetrant 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 penetrate into the CNS.11 Using another measure of CNS druglikeness, 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 recent review of methods used for predicting drug CNS penetration, Pike found CNS penetration correlated with lower molecular 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. In order to assess the possibility of contrasting ligandreceptor binding interactions or poses resulting from the structural 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 calculations were performed using the known X-ray crystallographic structure of the kappa opioid receptor in complex with JDTic.14,15 An overlay of the calculated binding poses of compounds 1 and 2, and the experimental binding pose of JDTic is illustrated in Figure 2. Receptor residue-ligand interactions are summarized in the two-dimensional interaction diagrams (Figure 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 tetrahydroquinoline hydroxy of compounds 1 and 2 participates in a hydrogen bond with a receptor site water molecule as observed in the JDTic X-ray 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 overlap 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 diverges from that of both compound 1 and JDTic in that the relative positions of the isopropyl group and the terminal six-
2
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membered ring are exchanged. In addition, this calculated conformational change suggests the possibility of new binding interactions for compound 2. A possible cation-aromatic 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.
In summary, we found that 1, which has only a simple piperidine ring where JDTic has a structurally complex trans3,4-dimethyl-4-(3-hydroxyphenyl)piperidine group was still a pure opioid receptor antagonist and has a Ke = 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 which does not have the piperidine amino group that is present in 1 has a Ke = 0.14 nM at the κ and is 1730- and 4570-fold selective for the KOR relative to the µ and δ opioid receptors, respectively. Docking studies of compounds 1 and 2 to the hKOR crystal structure of JDTic revealed differences and similarities of the binding interaction of 1 and 2 to each other as well as to JDTic. 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 compounds 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 development.
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 side-chains (gray) and waters (dark blue) are also illustrated. Hydrogen bonds are show as yellow dashed-lines.
Table 1. Comparison of the Inhibition of Agonist-Stimulated [35S]GTPγS Binding in Cloned Human µ, δ, and κ Opioid Receptors for Compounds 1 and 2 to those of JDTic, LY2456302a Ke (nM)a µ, DAMGO
δ, DPDPE
κ, U69,593
µ/κ
δ/κ
JDTic
25 ± 4
74 ± 2
0.02 ± 0.01
1250
3700
1
144 ± 37
>3000
6.8 ± 2.1
21
>440
2
242 ± 36
640 ± 170
0.14 ± 0.03
1730
4570
12.3 ± 1.0
240 ± 73
0.10 ± 0.03
123
2400
17.4
110
0.81
21
136
10 LY2456302
b
a
Ke values are the mean ± SEM of at least three independent experiments performed in duplicate. Neither 1 nor 2 had any agonist activity at 10 µM. 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
JDTic
TPSA
clogP
logBB
CNS MPO
MW
84.83
3.60
-0.57
3.1
465.6
2
61.36
4.0
-0.16
3.7
344.5
LY2456302
55.56
5.63
0.17
2.9
418.5
chemical properties is given. This information is available free of charge via the Internet at http://pubs.acs.org.
ASSOCIATED CONTENT Supporting Information Experimental procedures for the synthesis of 1 and 2, analytical data, [35S]GTPγS binding methods and calculation of physio-
AUTHOR INFORMATION Corresponding Author *F. Ivy Carroll, Ph.D.
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Research Triangle Institute Post Office Box 12194 Research Triangle Park, NC 27709-2194 Telephone: 919 541-6679 Fax: 919 541-8868 Email: [email protected]
Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Funding Sources This research was supported by the National Institute on Drug Abuse Grant DA12001).
ACKNOWLEDGMENT We thank Keith Warner and Tiffany Langston for conducting the in vitro testing.
ABBREVIATIONS [35S]GTPγS, sulfur-35 guanosine-5´-O-(3-thio)triphosphate; DAMGO, [D-Ala2,MePhe4,Gly-ol5]enkephalin; DPDPE, [DPen2,D-Pen5]enkephalin; U69,593, (5α,7α,8β)-(–)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro-[4.5]dec-8-yl]benzeneacetamide; EDC, 1-ethyl-3-(3-dimethylaminopropyl)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)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)1,2,3,4-tetrahydro-3-isoquinolinecarboxamide as a novel potent and selective opioid kappa receptor antagonist. J. Med. Chem. 2003, 46, 3127-3137. (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 trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity. J. Med. Chem. 2001, 44, 2687-90. (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 kappa-opioid receptor antagonist. Eur. J. Pharmacol. 2004, 501, 111-119. (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 cocaine-seeking induced by footshock
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stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl.) 2005, 183, 118-126. (5) Knoll, A. T.; Meloni, E. G.; Thomas, J. B.; Carroll, F. I.; Carlezon, W. A., Jr. Anxiolytic-like effects of κ-opioid receptor antagonists in models of unlearned and learned fear in rats. J. Pharmacol. Exp. Ther. 2007, 323, 838-845. (6) Deehan Jr, G. A.; McKinzie, D. L.; Carroll, F. I.; McBride, W. J.; Rodd, Z. A. The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats. Pharmacol. Biochem. Behav. 2012, 101, 581-587. (7) Jackson, K. J.; Carroll, F. I.; Negus, S. S.; Damaj, M. I. Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse. Psychopharmacology (Berl.) 2010, 210, 285-294. (8) 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 3- and 4-methyl substituents. Bioorg. Med. Chem. 2015, 23, 6379-88. (9) Rorick-Kehn, L. M.; Witkin, J. M.; Statnick, M. A.; Eberle, E. L.; McKinzie, J. H.; Kahl, S. D.; Forster, B. M.; Wong, C. J.; Li, X.; Crile, R. S.; Shaw, D. B.; Sahr, A. E.; Adams, B. L.; Quimby, S. J.; Diaz, N.; Jimenez, A.; Pedregal, C.; Mitch, C. H.; Knopp, K. L.; Anderson, W. H.; Cramer, J. W.; McKinzie, D. L. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology 2014, 77, 131144. (10) Summerfeld, S. G.; Read, K.; Begley, D. J.; Obradovic, T.; Hidalgo, I. J.; Coggon, S.; Lewis, A. V.; Porter, R. A.; Jeffrey, P. Central nervous system drug disposition: The relationship between in situ brain permeability and brain free fraction. J. Pharmacol. Exp. Ther. 2007, 322, 205-213. (11) Ghose, A. K.; Herbertz, T.; Hudkins, R. L.; Dorsey, B. D.; Mallamo, J. P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 2012, 3, 50-68. (12) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 2010, 1, 43549. (13) Pike, V. W. Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging. Curr. Med. Chem. 2016, 23, 1818-69. (14) PDB: 4DJH, Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X. P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human kappa-opioid receptor in complex with JDTic. Nature 2012, 485, 32732. (15) Surflex-Dock version 2.7, Jain, A. N. Surflex: fully automatic flexible molecular docking using a molecular similaritybased search engine. J Med Chem 2003, 46, 499-511. (16) Schrödinger Release 2017-1: Maestro, Schrödinger, LLC, New York, NY, 2017. In.
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OH
OH
HO HO
HO
N
N
N H
O
HO
NH O
N H
NH O 1
N H
N
NH O 2
N H
JDTic
NH O 10
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N
NH2 O F LY2456302
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Scheme 1 119x38mm (289 x 289 DPI)
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Scheme 2 156x39mm (288 x 289 DPI)
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Figure 2 716x761mm (72 x 72 DPI)
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Graphical Abstract 564x564mm (72 x 72 DPI)
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