1-Substituted 4-(3-Hydroxyphenyl)piperazines are pure opioid receptor antagonists

Article abstract of DOI:10.1021/ml100126b

This report describes the discovery that 1-substituted 4-(3-hydroxyphenyl) piperazines are pure opioid receptor antagonists. Compounds in this new series include N-phenylpropyl (3S)-3-methyl-4-(3-hydroxyphenyl)piperazine and (3R)-3-methyl-4-(3-hydroxyphenyl)piperazine, both of which display low nanomolar potencies at μ, δ, and κ receptors and pure antagonist properties in a [³⁵S]GTPγS assay.

Full text of DOI:10.1021/ml100126b

pubs.acs.org/acsmedchemlett
1-Substituted 4-(3-Hydroxyphenyl)piperazines
Are Pure Opioid Receptor Antagonists
F. Ivy Carroll,* Juan Pablo Cueva, James B. Thomas, S. Wayne Mascarella, Scott P. Runyon, and
ꢀ
Hernan A. Navarro
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194
ABSTRACT This report describes the discovery that 1-substituted 4-(3-hydroxy-
phenyl)piperazines are pure opioid receptor antagonists. Compounds in this new
series include N-phenylpropyl (3S)-3-methyl-4-(3-hydroxyphenyl)piperazine
and (3R)-3-methyl-4-(3-hydroxyphenyl)piperazine, both of which display low nano-
molar potencies at μ, δ, and κ receptors and pure antagonist properties in a [35S]GTPγS
assay.
KEYWORDS Opioid antagonists, 4-(3-hydroxyphenyl)piperazines
he opioid receptors, μ, δ, and κ, and the opioid-like
receptor ORL-1 belong to the superfamily of G-protein
coupled receptors (GPCRs) that possess seven helical
N-functionalized piperazine ring system to that in the piper-
idine ring of the 3,4-dimethyl-4-(3-hydroxyphenyl)piper-
idine class of compounds would provide more synthetically
accessible pure opioid antagonists. These prospects were
strengthened by a report by Komoto et al.20 which described
arylpiperazines such as 6a,b as having nanomolar binding
affinity at μ opioid receptors but did not present information
regarding their functional antagonist properties.
We discovered that 1-substituted 4-(3-hydroxyphenyl)piper-
azines (5) are pure opioid receptor antagonists (see Table 1
for structures of 5a-i). At present, there are few reported
classes of pure opioid receptor antagonists; the opiate class,
represented by naloxone (1a), naltrexone (1b), and the
N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidines,
represented by alvimopan, LY255,582, and JDTic, are the
most studied of non-peptide pure opioid receptor antago-
nists known21 (see ref 21 for a recent review). Our discovery
that 1-substituted 4-(3-hydroxyphenyl)piperazines (5) are
pure opioid receptor antagonists will add an additional
example of this important class of compounds.
Compounds 5a-f were synthesized by the reaction seq-
uence shown in Scheme 1. The tert-butoxycarbonyl-protected
starting piperazines 7a-e were commercially available, or
easily prepared by treating the appropriate piperazine with
di-tert-butylpyrocarbonate [(Boc)2O] or 2-tert-butoxycarba-
myloxyimino-2-phenylacetonitrile (Boc-ON) using standard
conditions. The piperazine needed for the preparation of 7e
was synthesized according to reported methods.22,23 tert-
Butoxycarbonyl-protected piperazines 7b,c were coupled to
3-bromoanisole under palladium-catalyzed conditions to
give arylpiperazines 8b,c. Arylation of 7d,e gave higher
yields when the arylation conditions reported by Bolliger
and Frech24 using potassium hexamethyldisilazide in dry
T
trans-membrane spanning domains in their architecture.1
These opioid receptors have been extensively studied, and
thousands of compounds have been synthesized and eval-
uated by in vitro binding and functional assays as well as by
animal models.2 An integral part of the effort to characterize
the opioid receptor system has been the discovery of potent,
pure antagonists. Naloxone (1a) and naltrexone (1b), both
competitive antagonists at μ, δ, and κ opioid receptors,3 have
been used extensively as pharmacological tools to identify
and characterize opioid systems. Additionally, naloxone is
approved to treat heroin overdose and to reverse respiratory
depression caused by morphine.3 Naltrexone is used to treat
heroin and alcohol abuse.4,5
In 1978, Zimmerman and co-workers reported the dis-
covery of a structurally unique series of opioid receptor pure
antagonists based on N-substituted analogues of 3,4-dimethyl-
4-(3-hydroxyphenyl)piperidine (2a, LY272922).6 Unlike nalo-
xone (1a) and naltrexone (1b) where the antagonist activity
is dependent on the N-allyl or N-cyclopropylmethyl substituent,
all N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperi-
dines (2) including the N-methyl analogue 2b are opioid
receptor pure antagonists.6-10 A few of the more interesting
analogues include alvimopan (3), which is an FDA-approved
drug for GI motility disorder,11 LY255,582 (2d),9,12 which
was developed to treat obesity, and the selective κ opioid
receptor antagonist JDTic (4),13-16 which shows activity in rat
models of depression,17 anxiety,18 stress-induced cocaine
relapse,17 and nicotine withdrawal.19
Given that N-substituted analogues of 2a have been deve-
loped as opioid receptor antagonists of clinical relevance, we
initiated a program to identify new scaffolds that avoided
lengthy chiral syntheses and could be readily functionali-
zed by expanding the SARs surrounding this subset of opioid
antagonists. N-Substituted 4-(3-hydroxyphenyl)piperazines
(5) were identified with the expectation that a similarly
Received Date: June 1, 2010
Accepted Date: July 5, 2010
Published on Web Date: July 09, 2010
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1,4-dioxane were employed. Removal of the tert-butoxycar-
bonyl group and demethylation were effected by treatment of
under palladium-catalyzed conditions to yield 16. Treatment
of 16 with boron tribromide in methylene chloride at -78 °C
effected removal of the tert-butoxycarbonyl group and de-
methylation of the methyl ether to give 17. Reductive alkyl-
ation of 17 using 3-phenylpropionaldehyde and sodium
triacetoxyborohydride in 1,2-dichloroethane afforded the
desired compound 5g.
Measures of opioid receptor antagonism and specificity
were obtained by monitoring the ability of selected test com-
pounds to inhibit stimulation of [35S]GTPγS binding pro-
duced by the selective agonists (D-Ala,2MePhe,4Gly-ol5)enke-
phalin (DAMGO, μ receptor), cyclo[D-Pen,2D-Pen5]enkephalin
(DPDPE, δ), and N-methyl-N-[(5R,7S,8S)-7-(1-pyrrolidinyl)-
1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593, κ) in
cloned human receptors (Table 1).
The 1-substituted 4-(3-hydroxyphenyl)piperazines (5a-f)
are pure opioid receptor antagonists that differ structurally in
two ways from the N-substituted 3,4-dimethyl-4-(3-hydro-
xyphenyl)piperidines (2). They have a nitrogen atom in
place of carbon atoms at position 4 of the six-membered
ring (relative to the piperidine ring) and do not have a
4-methyl substituent. Similar to N-methyl-3,4-trans-dimethyl-
4-(3-hydroxyphenyl)piperidine (2b), the N-methyl substi-
tuted (2S)-methyl piperazine analogue 5f is a pure opioid
antagonist. Changing from N-methyl to N-phenylpropyl gives
5b, which had Ke values of 0.88, 13.4, and 4.09 nM at the μ,
δ, and κ opioid receptors, respectively. These data are similar
to the Ke values obtained for N-phenylpropyl (3R,4R)-3,4-
dimethyl-4-(3-hydroxyphenyl)piperidine (2c).
The (3R)-methyl piperazine analogue 5c is also a pure
opioid receptor antagonist with Ke values of 1.01, 6.99, and
1.57 nM at the μ, δ, and κ opioid receptors, respectively.
Somewhat surprisingly, the piperazine analogue 5a, which
does not have a methyl substituent at the 3-position of the
piperazine ring, was also a pure opioid receptor antagonist,
with Ke values of 8.47, 34.3, and 36.8 nM at the μ, δ, and κ
opioid receptors, respectively. These results contrast with the
structure-activity information of compounds in the N-methyl
4-(3-hydroxyphenyl)piperidine series: the cis-3,4-dimethyl-
piperidine analogue 18a is reported to be a mixed agonist-
antagonist, and the 3-desmethyl analogue 18b is a morphine-
like agonist.6,26
8a-e with concentrated HBr or boron tribromide to give
9a-e. Reductive alkylation of 9a-e using 3-phenylpropio-
naldehyde and sodium triacetoxyborohydride in 1,2-dichloro-
ethane yielded the desired compounds 5a-e. Reductive
alkylation of 9b using formalin and Raney nickel under a
hydrogen atmosphere yielded 5f.
Compounds 5g,h were synthesized by the routes shown in
Scheme 2. Compound 1025 was coupled to 3-bromoanisole
under palladium-catalyzed conditions to give 11. Subjection
of 11 to palladium on carbon in refluxing aqueous acetic acid
removed the N-allyl-protecting group to give 12. Treatment
of 12 with boron tribromide in methylene chloride at -78 °C
affected demethylation of 12 to give the phenol 13. Reduc-
tive alkylation of 13 using 3-phenylpropionaldehyde and
sodium triacetoxyborohydride in 1,2-dichloroethane yielded
5h. Treatment of 10 with (Boc2)O in methylene chloride
containing triethylamine gives the N-allyl, N-Boc-protected
piperazine 14. Subjection of 14 to palladium on carbon in
refluxing aqueous acetic acid selectively removed the N-allyl
group to give 15. Compound 15 was coupled to 3-bromoanisole
The 1-phenylpropyl dimethylpiperazines (5d,e,g,h) all had
higher Ke values at all three opioid receptors than the 1-phenyl-
propyl monomethylpiperazines (5b and 5c). All compounds
(5a-f) of this class thus far tested are nonselective opioid
receptor antagonists.
Combining SAR studies of the N-substituted 4-(3-hydro-
1
xyphenyl)piperidine class of compounds with their H and
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Table 1. Comparison of Inhibition of Agonist Stimulated[35S]GTPγS Binding in Cloned Human μ,δ,andκOpioid Receptors for 1b,2b,c,and5a-h.
Kea (nM)
compd
structure
R1
R2
R3
R4
μ, DAMGO
δ, DPDPE
κ, U69,593
1b
2b
2c
5a
5b
5c
5d
5e
5f
3.6 ( 1.0
61 ( 11
4.6 ( 1.5
A
A
B
B
B
B
B
B
B
B
CH3
29.3 ( 3.4
0.1 ( 0.02
8.47 ( 1.42
0.88 ( 0.03
1.01 ( 0.24
1650b
681 ( 241
0.9 ( 0.32
34.3 ( 5.8
13.4 ( 4.2
6.99 ( 2.3
9000 ( 3200c
23.4 ( 6.0c
NAd
134 ( 27.1
0.88 ( 0.17
36.8 ( 16.8
4.09 ( 0.79
1.57 ( 0.34
123 ( 58
C6H5(CH2)3
C6H5(CH2)3
C6H5(CH2)3
C6H5(CH2)3
C6H5(CH2)3
C6H5(CH2)3
CH3
H
H
H
H
H
H
H
H
(S)-CH3
(R)-CH3
(S)-CH3
(S)-CH3
(S)-CH3
(S)-CH3
(R)-CH3
(S)-CH3
H
H
H
H
(S)-CH3
H
17.9 ( 7.7
508 ( 26
6.14 ( 1.7
18.0 ( 3.9
19.5 ( 7.9
194 ( 32.3
4.25 ( 0.82
22.9 ( 5.6
5g
5h
(R)-CH3
(S)-CH3
C6H5(CH2)3
C6H5(CH2)3
55.3 ( 3.2
180 ( 68
a Data are from the mean ( SE from at least three experiments. b Data from one experiment. c Data from two experiments. d NA =>10 μM.
Scheme 1a
a (a) 3-Bromoanisole, Pd2(dba)3, KOtBu, P(tBu)3, toluene, 100 °C, 18 h; (b) KN(Si(CH3)3)2, 3-bromoanisole, 1,4-dioxane 100 °C, 2 h; (c) BBr3,
CH2Cl2, -78 °C, 4 h; (d) HBr (48%) reflux; (e) C6H5(CH2)2CHO, Na(OAc)3BH, Et3N, DCE; (f) Raney Ni, H2CO, H2, EtOH.
13C NMR properties and conformational energy analyses,
Zimmerman et al. concluded that the opioid antagonist
activity of this class of compounds is mediated through the
equatorial phenyl low-energy conformation.27 Conforma-
tional energy analysis of the 4-(3-hydroxyphenyl)piperizines
5a and 5c shows that the phenyl equatorial conformers are
favored by ca. 2 kcal/mol.
In summary, 1-substituted 4-(3-hydroxyphenyl)piperizines
were found to be pure opioid receptor antagonists with poten-
cies at the μ, δ, and κ opioid receptors in a [35S]GTPγS assay
similar to the potencies of N-substituted 4-(3-hydroxyphe-
nyl)piperidines. Comparison of the SAR data of compounds
in the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
series with the activities of compounds 5a-h makes evident
that, despite the isosteric resemblance between these two
templates, there are significant differences between the res-
pective manners in which ligands from these classes interact
with opioid receptors to produce antagonist effects. The
relatively simple synthesis of this new class of opioid recep-
tor antagonists will allow efficient production of analogues.
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Scheme 2a
a (a) 3-Bromoanisole, Pd2(dba)3, KOtBu, P(tBu)3, toluene, 110 °C, sealed vessel; (b) Pd/C, CH3CO2H, H2O, reflux; (c) BBr3, CH2Cl2, -78 °C;
(d) C6H5(CH2)3CHO, Na(OAc)3BH, Et3N, DCE; (e) (Boc)2O, CH2Cl2, Et3N.
Efforts in our laboratories are currently being directed toward a
more comprehensive understanding of the structure-activity
relationships of compounds in this new series.
(7)
Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.; Partilla, J. S.;
Xu, H.; McCullough, K. B.; Dersch, C. M.; Cantrell, B. E.;
Zimmerman, D. M.; Carroll, F. I. Investigation of the N-substituent
conformation governing potency and μ receptor subtype-selec-
tivity in (þ)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine
opioid antagonists. J. Med. Chem. 1998, 41, 1980–1990.
Zimmerman, D. M.; Leander, J. D.; Cantrell, B. E.; Reel, J. K.;
Snoddy, J.; Mendelsohn, L. G.; Johnson, B. G.; Mitch, C. H.
Structure-activity relationships of the trans-3,4-dimethyl-
4-(3-hydroxyphenyl)piperidine antagonists for μ and κ opioid
receptors. J. Med. Chem. 1993, 36, 2833–2841.
Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.; Shaw, W. N.;
Wong, D. T.; Cantrell, B. E.; Johnson, B. G.; Reel, J. K.; Snoddy,
J. D.; Takemori, A. E.; Zimmerman, D. M. 3,4-Dimethyl-4-(3-
hydroxyphenyl)piperidines: Opioid antagonists with potent
anorectant activity. J. Med. Chem. 1993, 36, 2842–2850.
SUPPORTING INFORMATION AVAILABLE Experimental
procedures for the synthesis and elemental analysis data for
5a-f. This material is available free of charge via the Internet at
http://pubs.acs.org.
(8)
(9)
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Phone: (919) 541-6679. Fax: (919) 541-8868. E-mail:
fic@rti.org.
(10) Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.; Schoepp,
D. D.; Johnson, B. G.; Leander, J. D. Discovery of a potent,
peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphe-
nyl)piperidine opioid antagonist for the treatment of gastro-
intestinal motility disorders. J. Med. Chem. 1994, 37, 2262–
2265.
Funding Sources: This research was supported by the National
Institute on Drug Abuse, Grant DA 09045.
REFERENCES
(1)
Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley,
P. B.; Portoghese, P. S.; Hamon, M. International Union of
Pharmacology. XII. Classification of opioid receptors. Phar-
macol. Rev. 1996, 48, 567–592.
(11) Delaney, C. P.; Yasothan, U.; Kirkpatrick, P. Alvimopan. Nat.
Rev. Drug Discovery 2008, 7, 727–728.
(12) Statnick, M. A.; Suter, T. M.; Gackenheimer, S. L.; Emmerson,
P. J.; Quimby, S. J.; Gehlert, D. R.; Wheeler, W. J.; Mitch, C. H.
Naþ-dependent high affinity binding of [3H]LY515300, a 3,4-
dimethyl-4-(3-hydroxyphenyl)piperidine opioid receptor in-
verse agonist. Eur. J. Pharmacol. 2003, 482, 139–150.
(13) Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman, R. B.;
Mascarella, S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.; McCullough,
K. B.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification
of an opioid κ receptor subtype-selective N-substituent for
(þ)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine. J. Med.
Chem. 1998, 41, 5188–5197.
(2)
Aldrich, J. V.; Vigil-Cruz, S. C. Narcotic Analgesics. In Burger's
Medicinal Chemistry and Drug Discovery, 6th ed.; Abraham,
D. J., Ed.; John Wiley & Sons: New York, NY, 2003; Vol. 6,
Chapter 7, pp 329-481.
(3)
(4)
Kreek, M. J.; LaForge, K. S.; Butelman, E. Pharmacotherapy of
addictions. Nat. Rev. Drug Discovery 2002, 1, 710–726.
Soyka, M.; Rosner, S. Opioid antagonists for pharmacological
treatment of alcohol dependence;a critical review. Curr.
Drug Abuse Rev. 2008, 1, 280–291.
(5)
(6)
White, J. M.; Lopatko, O. V. Opioid maintenance: a compara-
tive review of pharmacological strategies. Expert Opin. Phar-
macother. 2007, 8, 1–11 .
Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong, D. T.
New structural concepts for narcotic antagonists defined in a
4-phenylpiperidine series. Nature 1978, 275, 332–334.
(14) 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-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-
methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide
r
2010 American Chemical Society
368
DOI: 10.1021/ml100126b ACS Med. Chem. Lett. 2010, 1, 365–369
|

pubs.acs.org/acsmedchemlett
as a novel potent and selective opioid kappa receptor
antagonist. J. Med. Chem. 2003, 46, 3127–3137.
(15) 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)piperi-
dine derivative to possess highly potent and selective opioid
kappa receptor antagonist activity. J. Med. Chem. 2001, 44,
2687–2690.
(16) 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 κ-opioid recep-
tor antagonist. Eur. J. Pharmacol. 2004, 501, 111 –119.
(17) Beardsley, P. M.; Howard, J. L.; Shelton, K. L.; Carroll, F. I.
Differential effects of the novel kappa opioid receptor anta-
gonist, JDTic, on reinstatement of cocaine-seeking induced
by footshock stressors vs cocaineprimesand itsantidepressant-
like effects in rats. Psychopharmacology (Berlin, Ger.) 2005,
183, 118–126.
(18) Knoll, A. T.; Meloni, E. G.; Thomas, J. B.; Carroll, F. I.; Carlezon,
W. A., Jr. Anxiolytic-Like Effects of κ-Opioid Receptor Antago-
nists in Models of Unlearned and Learned Fear in Rats.
J. Pharmacol. Exp. Ther. 2007, 323, 838–845.
(19) Jackson, K. J.; Carroll, F. I.; Negus, S. S.; Damaj, M. I. Effect of
the selective kappa-opioid receptor antagonist JDTic on nico-
tine antinociception, reward, and withdrawal in the mouse.
Psychopharmacology (Berlin, Ger.) 2010.
(20) Komoto, T.; Okada, T.; Sato, S.; Niino, Y.; Oka, T.; Sakamoto, T.
New mu-opioid receptor agonists with piperazine moiety.
Chem. Pharm. Bull. (Tokyo) 2001, 49, 1314–1320.
(21) Goodman, A. J.; Le Bourdonnec, B.; Dolle, R. E. Mu opioid
receptor antagonists: recent developments. ChemMedChem
2007, 2, 1552–1570.
(22) Tanatani, A.; Mio, M. J.; Moore, J. S. Chain length-dependent
affinity of helical foldamers for a rodlike guest. J. Am. Chem.
Soc. 2001, 123, 1792–1793.
(23) Ueda, T.; Saito, M.; Kato, T.; Izumiya, N. Facile synthesis of
cyclic dipeptides and detection of racemization. Bull. Chem.
Soc. Jpn. 1983, 56, 568–672.
(24) Bolliger, J. L.; Frech, C. M. Transition metal-free amination of
aryl halides;A simple and reliable method for the efficient
and high-yielding synthesis of N-arylated amines. Tetrahe-
dron 2009, 65, 1180–1187.
(25) Janetka, J. W.; Furness, M. S.; Zhang, X.; Coop, A.; Folk, J. E.;
Mattson, M. V.; Jacobson, A. E.; Rice, K. C. Enantioconvergent
synthesis of (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, an
intermediate to delta-opioid receptor ligands. J. Org. Chem.
2003, 68, 3976–3980.
(26) McElvain, S. M.; Clemens, D. H. Piperidine derivatives. XXX.
1,4-Dialkyl-4-arylpiperidines. J. Am. Chem. Soc. 1958, 80,
3915–3923.
(27) Zimmerman, D. M.; Smits, S. E.; Hynes, M. D.; Cantrell, B. E.;
Reamer, M.; Nickander, R. Structural requirements for affi-
nity and intrinsic activity at the opiate receptor defined in
4-phenylpiperidine and related series. In Problems of Drug
Dependence, 1981, Proceedings of the 43rd Annual Scientific Meet-
ing of the Committee on Problems of Drug Dependence, Inc.;
Harris, L. S., Ed.; National Institute on Drug Abuse: Rockville,
MD, 1982; NIDA Research Monograph 41; pp 112-11 8 .
r
2010 American Chemical Society
369
DOI: 10.1021/ml100126b ACS Med. Chem. Lett. 2010, 1, 365–369
|