γ-Aminobutyric acid(C) (GABAC) selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: Amides and hydroxamates

Article abstract of DOI:10.1021/jm4006548

Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABA_C, the most potent being 4-ACPHA (10a, IC₅₀ = 13 μM) and 4-ACPAM (11a, IC ₅₀ = 10 μM). This provides evidence that a zwitterionic structure is not essential for GABA_C antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.

Full text of DOI:10.1021/jm4006548

Brief Article
pubs.acs.org/jmc
γ‑Aminobutyric Acid(C) (GABAC) Selective Antagonists Derived from
the Bioisosteric Modification of 4‑Aminocyclopent-1-enecarboxylic
Acid: Amides and Hydroxamates
Katherine E. S. Locock,*,†,§ Izumi Yamamoto,‡ Priscilla Tran,† Jane R. Hanrahan,‡ Mary Chebib,‡
Graham A. R. Johnston,† and Robin D. Allan†
†Adrien Albert Laboratory of Medicinal Chemistry, Pharmacology, University of Sydney, NSW, Australia
‡Faculty of Pharmacy, University of Sydney, NSW, Australia
S
* Supporting Information
ABSTRACT: Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with
hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being
4-ACPHA (10a, IC50 = 13 μM) and 4-ACPAM (11a, IC50 = 10 μM). This provides evidence that a zwitterionic structure is not
essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.
As a result of GABA’s flexible backbone, it is able to adopt a
number of conformations when interacting with various
macromolecular targets. This characteristic of GABA can be
utilized to provide selective ligands through the generation of
conformationally restricted analogues. These use structures
such as double bonds, rings, or bulky substituents to restrict
molecule into conformations of GABA favored by a subset of
these sites. For instance, the introduction of a five-membered
ring structure allows the compound to mimic the binding mode
of GABA at GABAA and GABAC receptors, thus driving
selectivity for these subtypes over that of GABAB receptors.
Such compounds have been synthesized, an example being 2,
which displays antagonism at the GABAC receptor, however, it
also has GABAA agonist activity.8,9
INTRODUCTION
GABA (1, Figure 1) is the major inhibitory neurotransmitter of
the mammalian central nervous system (CNS), with its effects
■
Previous work has investigated the effect of manipulating the
acidic and basic moieties of these restricted analogues. This has
led to the synthesis of a series of phosphinic acid derivatives
(4)10,11 based around the structures of 2 and 3. The
replacement of a carboxylic acid by a phosphinic acid retains
hydrogen and ionic bonding capability but also allows for the
introduction of alkyl substituents. It is thought that these alkyl
side chains drive the GABAC selectivity, with no GABAA
activity observed with this class of compounds. As a result, a
lipophilic pocket is proposed at the GABAC receptor site which
is able to accommodate these groups.7,11 This raises the
question as to whether similar groups included in the structure
of 2 could also lead to potent and/or selective GABAC agents.
Therefore, the present study sought to bioisosterically replace
the carboxylate group of 2 with an alternate functional group to
allow the introduction of alkyl and aryl groups at this position.
It has previously been noted that a zwitterionic structure is
important for activity at GABA receptors,11−14 and hence stage
one of the present study investigated a functional group
expected to be partly ionized at physiological pH.
Figure 1. GABA and various conformationally restricted analogues: 2,
a GABAA agonist and GABAC antagonist, and 3 and 4, selective
GABAC antagonists.
mediated through the regulation of ionotropic GABAA and
GABAC receptors as well as the metabotropic GABAB.1 There
has been recent interest in the GABAC receptor and its
implications on memory formation due to its long ion channel
opening time,2 location in the hippocampus,3 and evidence of
involvement in ammonia-induced apoptosis of hippocampal
cells.4 Their role in cognition has been supported by findings
that GABAC antagonists can enhance learning in chicks5 and
mice.6
Few selective GABAC receptor antagonists have been
identified, hence much of the structure−activity relationships
at GABAC receptors remain unclear. This is due to the limited
diversity of GABAC selective antagonists, where most are
derived from phosphinic acids.7 It is therefore crucial for a
wider range of compounds to be identified in order to further
the understanding of GABAC structure−activity relationships,
as this may lead to the development of novel therapeutics.
Received: May 2, 2013
Published: June 11, 2013
© 2013 American Chemical Society
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Hydroxamic acids, with pKa values in the order of 9, would
be expected to be approximately 1% ionized under physio-
logical conditions. O-Substitution changes the pKa only
slightly,15 hence the hydroxamic acid group appeared to fulfill
the requirements of this study, namely a functional group that
could be expected to be partially ionized at physiological pH,
leaving open the possibility of ionic binding as well as serving as
a point for the introduction of substituents.
To further explore the relative importance of an acidic group
and consequently a zwitterionic structure for activity, stage two
of this study involved replacing the carboxylic acid of 2 with an
alternate group expected to be un-ionized at physiological pH.
Amides typically have pKa values over 1516 and so would be
effectively un-ionized at physiological pH but would, however,
be capable of forming similar hydrogen bonding to 2.
Therefore, it was thought that testing amide derivatives of 2
would provide more information on the importance of a
zwitterionic structure for activity at GABA receptor sites. We
also wished to further explore the possibility of introducing
various substituents, the amide serving as a point for
substitution. This may further characterize the proposed
hydrophobic cavity at GABAA and GABAC receptors.
lactam 5 (2-azabicyclo[2.2.1]hept-5-en-3-one) with methanol
and thionyl chloride gave the methyl ester hydrochloride (6).
Treatment of this intermediate with di-tert-butyl dicarbonate
and triethylamine produced the protected amino ester (7),
which was isomerized with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) to give the conjugated methyl 4-(tert-
butoxycarbonylamino)cyclopent-1-enecarboxylate (8) as a
white, crystalline solid in good yield. The methyl ester 8 was
selectively hydrolyzed with base to give 9, a key intermediate in
this study, as it was used to generate all final target compounds.
The Boc protecting group of 9 was hydrolyzed to give parent
compound 2 as a white crystalline solid after isolation using a
Dowex 50 (H+) ion exchange column.
Hydroxamic acid derivatives (10a−d) were prepared via a
mixed anhydride method. 9 was treated with i-butyl
chloroformate in the presence of base and subsequent addition
of the hydroxylamine of interest. In the case of the
unsubstituted 10a, a commercially available, pyran-protected
hydroxylamine was used to limit attack on the mixed anhydride
to that by the free amine position of the hydroxylamine. Acidic
hydrolysis of protecting groups gave hydroxamates 10a−d.
Amide derivatives (11a−e) were prepared using a similar
method. The N-Boc acid (9) was treated with i-butyl
chloroformate to generate the mixed anhydride and subsequent
addition of the desired amine, followed by deprotection to give
11a−e. The activity of compounds 2, 10a−d, and 11a−e was
assessed using the two-electrode voltage clamp method in
Xenopus laevis oocytes expressing human recombinant GABAA
(α1β2γ2L), GABAB(1b,2), and ρ1 GABAC receptors. All
compounds were initially screened alone at a concentration
of 300 μM and then at a concentration of 300 μM in the
presence of a submaximal dose of GABA (EC50) to detect
either agonist or antagonist activity, respectively. Compounds
displaying the most potent effects at GABAC receptors
underwent further evaluation and a current concentration−
response curve generated in the presence of an EC50 GABA
concentration (1 μM).
This study aimed to synthesize hydroxamic and amide
analogues of 2. Testing of the unsubstituted derivatives 10a (4-
ACPHA) and 11a (4-ACPAM) would help to identify the
influence that the bioisosteric replacement would have on
activity when compared with the parent carboxylic acid, 2. A
series of substituted derivatives were also to be prepared (10b−
d and 11b−e) to assess the effect of alkyl and aryl substituents
on GABA receptor activation.
RESULTS AND DISCUSSION
■
The target compounds were synthesized according to Scheme
1. The route to intermediate 8 followed that reported
previously.17 In short, treatment of the commercially available
a
Scheme 1
All newly synthesized hydroxamate derivatives (10a−d)
displayed antagonist profiles at GABAC receptors (Table 1).
These compounds exhibited reduced activities at both GABAA
and GABAB receptors when compared with the parent
carboxylic acid 2. In particular, the unsubstituted hydroxamic
acid, 10a, displayed similar potency as an antagonist at GABAC
receptors but with superior selectivity when compared with the
parent 2. This indicates that the bioisosteric replacement of the
carboxylic acid moiety of 2 with a hydroxamic acid to give 10a
is well tolerated at the binding site and has resulted in a
selective GABAC antagonist. This is in spite of the fact that a
hydroxamic acid group would be expected to be approximately
only 1% ionized at physiological pH. While this is a small
proportion, it still leaves a possibility that it is the ionized form
of 10a−d that participates in binding at the receptor site. When
contrasting the activity of 10a with the other hydroxamates of
the series (10b−d) that incorporate an O-substituent, it can be
seen that O-substitution has led to a 7−12-fold reduction in
potency at the GABAC site. This shows that alkyl groups at this
position are not well tolerated at the receptor site, presumably
from interference with important binding interactions between
the hydroxamic acid and receptor. This is in contrast to findings
for the phosphinic acid derivatives, where alkyl groups are
thought to increase binding affinity at the site.12,13
a
Reagents and conditions: (i) SOCl2, MeOH, 0 °C; (ii) (Boc)2O,
Et3N, THF, 0 °C to rt; (iii) DBU, THF, rt; (iv) 0.5 M NaOH, THF;
(v) HCl, EtOAc; (vi) (1) i-BuOCOCl, TEA, −20 °C, (2) O-
(tetrahydro-2H-pyran-2-yl)hydroxylamine, −20 °C to rt; (vii) 6 M
HCl, MeOH; (viii) (1) i-BuOCOCl, TEA, −20 °C, (2) NHOR, −20
°C to rt; (ix) (1) i-BuOCOCl, TEA, −20 °C, (2) H2NR, −20 °C to rt.
Compounds 11a−e were generated through the bioisosteric
introduction of an amide group at the carboxylic acid position
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Table 1. Pharmacological Data
GABAA (α1β2γ2L) activity
GABAB(1b,2) activity
% inhibition
GABAC ρ1 activity
c
% GABAmax
% inhibition
(at 300 μM against GABA
% GABAmax
response
IC50 or % inhibition
response
(at 300 μM)
(at 300 μM against GABA (at 300 μM against GABA
a
b
a
b b
compd
R =
EC50 dose)
(at 300 μM)
EC50 dose)
EC50 dose)
2
OH
59.7 2.7%
4.3 0.1%
6.3 0.7%
2.5 0.1%
1.7 0.9%
75.3 7.5%
23.0 3.8%
31.0 3.3%
16.3 2.2%
33.0 5.5%
6.6 0.7 μM
12.9 1.1 μM
81.5 2.9 μM
153.0 15.6 μM
115.3 9.7 μM
10a
10b
10c
10d
NHOH
NHOCH3
NHOCH3
NHOCH2CHCH2
11a
NH2
23.3 7.8%
5.2 0.7%
9.6 0.9 μM20
d
11b
11c
11d
11e
NHCH3
NA at 300 μM
NA at 300 μM
NA at 300 μM
NA at 300 μM
NA at 300 μM
3.2 2.0%
9.0 2.3%
3.3 1.2%
408.3 57.6 μM
570.0 54.8 μM
20.5 1.1%
NH(CH2)2CH3
NH(CH2)4CH3
NHPhCH3(p)
NA at 300 μM
NA at 300 μM
NA at 300 μM
27.0 7.5%
11.3 3.1%
a
b
Current produced by 300 μM of compound. Data are mean SEM (n = 3−5 oocytes). Percentage inhibition by 300 μM of compound of the
current produced by a submaximal dose of GABA (EC50). EC50 values for GABA for GABAA (α1β2γ2L), GABAB(1b,2), and ρ1 GABAC are 30, 1, and 1
μM, respectively. Data are mean SEM (n = 3−4 oocytes). Compound concentration which inhibits a submaximal dose of GABA (1 μM, EC50).
Data are mean SEM (n = 3−5 oocytes). NA is no activity observed up to given concentration.
c
d
of 2. In a similar manner to the hydroxamates, the
unsubstituted amide 11a displayed the greatest potency as an
antagonist at GABAC receptors (IC50 = 9.6 μM). 11a also has
similar potency to that of the parent compound 2 but with
reduced activity at GABAB receptors. At GABAA receptors, 11a
displayed very weak antagonist properties (23.3% inhibition at
300 μM), whereas 2 is a weak agonist at GABAA receptors
(59.7% of the GABAmax response at 300 μM). Hence, the
simple bioisosteric replacement of a carboxylic acid (2)
predominantly ionized at physiological pH by a neutral amide
(11a) has given a GABAC selective antagonist. This provides
clear evidence that a zwitterionic structure is not essential for
potent antagonist action at GABAC receptors. The N-alkyl and
N-aryl substituted amide derivatives 11b−e were also found to
act as GABAC antagonists but with greater than 40-fold
reduction in activity compared to the unsubstituted amide 11a,
for instance, 11e displays only 11.3% inhibition at 300 μM.
This indicates that substitution at this position does not appear
to be well tolerated at this site as it may sterically interfere with
important binding interactions.
With respect to GABAC potency, the introduction of N-
substituents to the amide derivatives (11b−e) was much less
successful than the O-substitution to give the hydroxamate
derivatives (10b−d). This observation may be explained by the
fact that N-substituents of the amide group compared with the
O-substituents of the hydroxamate are placed in different
relative positions. While both functional groups can adopt both
E and Z conformations, the hydroxamate places the O-
substituent one atom further away from the CO. This may
allow the group to access different residues available at the
receptor site compared to the amide derivatives.
state of ionization predominant at physiological pH. Structures
were docked, and solutions were selected as detailed in the
Supporting Information. All compounds were found to dock in
a similar way. They displayed hydrogen bond interactions with
residues at the receptor site. Docking results of key structures
are shown in Figure 2A−D. Results are in strong concordance
with observed experimental data.
In agreement with previous findings,7 the amino moiety of
each compound interacted with the tyrosine 198 residue
(Y198) while the carbonyl region in each displayed discrete
bonding arrangements. The oxygens of the carboxylic acid 2
(Figure 2A) formed two H-bonds to arginine 104 (R104), one
to serine 243 (S243), and another to Y198. The hydroxamic
acid 10a and amide 11a did not appear to interact with Y198
but forms additional bonds with other residues. In the case of
10a, it was found to interact more strongly with R104, with the
two oxygen atoms forming a total of three H-bonds with this
residue as shown in Figure 2B. The terminal oxygen formed an
addition bond with S243. It should also be pointed out that this
hydroxamic acid did appear to reside in the Z geometry as
predicted by previous studies.18,19 In contrast, amide 11a
(Figure 2C) formed the bulk of bonds with the carbonyl group,
forming two bonds to R104 and another to S243. Also
interestingly, the amide NH2 formed a hydrogen bond with
aspartate 164 (D164), a residue not utilized by either 2 or 10a.
This change may be explained by the difference in orientation
of the carboxamide group of 11a (seen to be approximately
perpendicular to the plane of the page in Figure 2C) when
compared with the carbonyl group of 2 (seen to be
approximately in the plane of the page in Figure 2A). Further
evidence for a different binding mode of 11a has been noted in
a previous study from our group involving ρ1 GABAC Y102
receptor mutants.20 These receptors are constitutively active,
allowing an investigation of the binding preference of various
GABAC agents for closed versus open receptor states. Of all the
cyclopentene agents tested (2, 3-ACPBPA (3-aminopropyl-
methyl-phosphinic acid) and 11a), 11a was the only compound
GABAC receptor ligand docking studies were performed to
help elucidate the molecular interactions underlying these
results using a TPMPA minimized N-terminal ligand-binding
domain homology model of the ρ1 GABAC receptor developed
previously by others in our group.7 Docking trials were
performed for both optical isomers of 2, 10a, and 11a using the
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found to explicitly act on receptors in the closed state. To
identify possible explanations for the loss of activity observed
for the alkyl and aryl derivatives 10b−d and 11b−e, fitting
results were compared with those obtained for 4 (R = n-butyl)
(Figure 2D), a previously described GABAC selective
antagonist. The n-butyl group of this compound is thought to
be accommodated by a lipophilic pocket available at the
binding site, serving to increase binding affinity. If the relative
position of this group is compared to the docking results
obtained for 10a and 11a, it can be seen that if terminal
substituents were introduced to the hydroxamic acid or amide
groups, this would place them in a different orientation relative
to that of the n-butyl group. This would render them unable to
access the lipophillic pocket and may in fact have introduced
steric hindrance, reducing binding affinity. This is echoed by
results obtained for all substituted derivatives in this study,
10b−d and 11b−e, showing reduced potencies in all cases.
Overall, docking results have provided a rationale for the
observed potencies of synthesized compounds. They also
provide further evidence that a zwitterionic structure is not
essential for activity at the GABAC receptor site. For strong
ligand−receptor interactions, the requirement is that a
compound has appropriate heteroatoms in the correct
orientation to participate in hydrogen bonding with residues
available at the receptor site and that at the nitrogen binding
site an ionic interaction is not essential.
CONCLUSION
■
This study identified two new classes of GABAC analogues
through the bioisosteric replacement of the carboxylic acid
moiety of 2 with either a hydroxamic acid (10a−d) or amide
(11a−e) group. These functional groups were chosen to allow
an investigation of the importance of a zwitterionic structure for
potent actions at GABAC receptors, as a hydroxamic acid would
be expected to be only partially ionized at physiological pH
while an amide would be expected to be nonionized.
All compounds from this study exhibited increased selectivity
for the GABAC, the most potent compounds being 10a (IC50
=
13 μM) and 11a (IC50 = 10 μM). While the potency of
compounds may sit just beyond that useful for clinical
applications, they serve as important pharmacological tools to
probe binding interactions at the GABAC site. 11a is of
particular interest, as it provides clear proof that for strong
ligand−receptor interactions at the GABAC site a zwitterionic
structure is not essential.
The discovery of two novel series of GABAC antagonists
serves to widen the current scope for compounds acting at this
site beyond those of phosphinic acid derivatives. Such
information is invaluable when piecing together a detailed
view of the structure−activity relationships and may lead to the
development of novel therapeutics that target the GABAC
receptor.
EXPERIMENTAL SECTION
■
For full details see Supporting Information. Purity of tested
compounds was assessed using analytical HPLC and found to be
≥95%.
Representative Procedure for the Synthesis of Derivatives
via the Mixed Anhydride Method. ( )-4-Aminocyclopent-1-
enecarboxamide (11a). Triethylamine (304 mg, 3 mmol) was
added to a solution of ( )-4-tert-butoxycarbonylaminocyclopent-1-
enecarboxylic acid (9, 341 mg, 1.5 mmol) in THF (30 mL) at 0 °C. i-
Butylchoroformate (338 mg, 2.5 mmol) was added dropwise, and the
solution left to stir for 15 min. Gaseous ammonia was bubbled through
Figure 2. GABAC receptor docking results for (A) 2, (B) 10a, (C)
11a, (D) 4 (R = n-butyl).
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the solution for 20 min and the reaction left to stir at 0 °C for a further
2 h. The reaction was concentrated in vacuo, diluted with ethyl acetate
(30 mL), and washed with aqueous sodium hydroxide (1M, 10 mL),
saturated citric acid (10 mL), and brine (10 mL). The organic fraction
was dried over sodium sulfate, and solvent was removed under reduced
pressure. The product was isolated using flash chromatography, eluting
with ethyl acetate/dichloromethane (10:1) to give ( )-tert-butyl 3-
carbamoylcyclopent-3-enylcarbamate (315 mg, 92% yield). tert-Butyl
3-carbamoylcyclopent-3-enylcarbamate (315 mg, 1.39 mmol) was
dissolved in a saturated solution of hydrochloric acid in ethyl acetate
and the resulting solution allowed to stir for 4 h. Solvent was removed
in vacuo and the product isolated using an ion-exchange column of
Dowex 50W (H+) (10 mL), eluting the amino amide with ammonia
(2M). This gave ( )-4-aminocyclopent-1-enecarboxamide (10a, 156
mg, 89% yield). Rf = 0.27 (4:1:1 n-butanol/acetic acid/water). 1H
NMR (300 MHz, D2O): δ 6.32 (1H, s, CH), 4.03−3.93 (1H, m,
CHNH2), 3.01−2.84 (2H, m, cyclopentene CHH and CHH), 2.56−
2.43 (2H, m, cyclopentene CHH and CHH). 13C NMR (300 MHz,
D2O): δ 171.1 (CO), 140.2 (CH), 136.0 (C), 50.9 (CHNH2),
42.3 (cyclopentene CH2), 40.5 (cyclopentene CH2). ESI-MS m/z
positive ion mode, 127 (55%, MH+), 110 (5%, MH+-NH3); negative
ion mode, 126 (20%, M+ − H). HPLC: tR = 3.61 min.
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GABA(C) receptors. Chem. Biol. Drug Des. 2008, 71, 306−327.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Full details of synthetic methods, spectroscopic data for
compounds, in vitro pharmacological testing, and molecular
modeling. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Kumar, R. J.; Chebib, M.; Hibbs, D. E.; Kim, H. L.; Johnston, G.
A. R.; Salam, N. K.; Hanrahan, J. R. Novel gamma-aminobutyric acid
rho(1) receptor antagonists: synthesis, pharmacological activity and
structure−activity relationships. J. Med. Chem. 2008, 51, 3825−3840.
(12) Crittenden, D. L.; Kumar, R. J.; Hanrahan, J. R.; Chebib, M.;
Jordan, M. J. T. Stabilization of zwitterions in solution: phosphinic and
phosphonic acid GABA analogues. J. Phys. Chem. A 2005, 109, 8398−
8409.
AUTHOR INFORMATION
Corresponding Author
*Phone: +61395458886. E-mail: katherine.locock@csiro.au.
■
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Chem. Eng. (N. Y.) 2012, 119, 9.
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Analogues Derived from 4-Aminocyclopent-1-enecarboxylic Acid.
Neurochem. Res. 2009, 34, 1698−1703.
Present Address
§CSIRO Materials Science and Engineering, Bayview Avenue,
Clayton, VIC 3168, Australia.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Heba Abdel-Halim for performing the GABAC
docking of 2, 10a, and 11a. We also thank Dr. Joe Liu for
HPLC analysis and Bruce Tattam for MS measures. K.L. and
I.Y. acknowledge the John A. Lamerberton Scholarship, and
K.L. acknowledges support from the Australian Postgraduate
Award Scheme.
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ABBREVIATIONS USED
■
4-ACPCA, 4-aminocyclopent-2-enecarboyxlic acid; 4-ACPHA,
4-amino-N-hydroxycyclopent-1-enecarboxamide; 4-ACPAM, 4-
aminocyclopent-1-enecarboxamide; TPMPA, 1,2,5,6-tetrahy-
dropyridin-4-yl(methylphosphinic acid)
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