Novel cyclic phosphinic acids as GABAC ρ receptor antagonists: Design, synthesis, and pharmacology

Article abstract of DOI:10.1021/ml1001344

Understanding the role of GABA_C receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABA_C receptor antagonists. A compound of high potency (19, K_B = 10 μM) and selectivity (greater than 100 times at ρ₁ GABA_C receptors as compared to α ₁β₂γ_2L GABA_A and GABA_B(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABA_C receptor antagonists with increased lipophilicity for future in vivo studies.

Full text of DOI:10.1021/ml1001344

pubs.acs.org/acsmedchemlett
Novel Cyclic Phosphinic Acids as GABA F Receptor
C
Antagonists: Design, Synthesis, and Pharmacology
†
†
‡
§
§
Navnath Gavande, Izumi Yamamoto, Noeris K. Salam, Tu-Hoa Ai, Peter M. Burden,
§
†
,†
Graham A. R. Johnston, Jane R. Hanrahan, and Mary Chebib*
†
‡
Faculty of Pharmacy, The University of Sydney, NSW, Australia, Schrodinger, Inc., 8910 University Center Lane, Suite 270,
§
San Diego, California, United States, and Adrien Albert Laboratory, Department of Pharmacology, The University of Sydney,
NSW, Australia
ABSTRACT Understanding the role of GABA receptors in the central nervous system
C
is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues
based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-
1
-hydroxy-phospholane 19 were investigated to obtain selective GABA receptor
C
antagonists. A compound of high potency (19, K =10 μM) and selectivity (greater
B
than 100 times at F GABA receptors as compared to R β γ GABA and GABA
1
C
1
2
2L
A
B(1b,2)
receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead
agents for developing into more potent and selective GABA receptor antagonists
C
with increased lipophilicity for future in vivo studies.
KEYWORDS γ-Aminobutyric acid, ligand-gated ion channels, GABA receptors,
cyclic phosphinic acids, two-electrode voltage clamp, F GABA homology model
1
C
minobutyric acid 1 (GABA 1, Figure 1) is the
The GABA receptor has distinct pharmacology, physio-
C
major inhibitory neurotransmitter in the mam-
logy, and subunit composition to that of GABA and GABA
A
B
γ
1,5,6
-
A
malian central nervous system (CNS) and is
receptors.
Consisting of homo-oligomeric or pseudohomo-
essential for the overall balance between neuronal excitation
oligomeric pentameric compositions of F subunits (F , F ,
1
2
1,2
5,7
and inhibition. GABA influences neurons via three major
classes of receptors that are grouped on the basis of their
subunit composition, gating properties, and pharmacologi-
cal profiles: GABA , GABA , and GABA (GABA F) receptors.
and F subunits) in mammals, the receptors are highly
expressed in many parts of the brain, including the superior
3
8
9
colliculus, cerebellum, hippocampus (high F subunit ex-
2
1
0
pression), and, most prominently, the retina (high F sub-
A
B
C
1
11
GABA and GABA receptors are ionotropic receptors, belonging
unit expression).
A
C
to the Cys loop family of ligand-gated ion channels, which also
incorporates nicotinic acetylcholine, strychnine-sensitive gly-
cine, serotonin type 3, and some invertebrate anionic gluta-
The first selective GABA receptor antagonist developed
C
was 1,2,5,6-tetrahydropyridine-4-yl-methyl-phosphinic acid
1
2
3 (TPMPA 3, Figure 1). TPMPA 3 has been shown to
1,2
13
mate receptors.
Both GABAA and GABAC receptors are
enhance memory in chicks, inhibit myopia development
1
4
15
chloride channels that mediate fast synaptic inhibition when
in chicks, modulate the sleep-waking behavior in rats,
and exert influence on the lateral nucleus of the amygdala
activated by GABA. In contrast, GABA receptors are members
B
1
6
of the family 3 class metabotropic receptors; these receptors
(LA). However, TPMPA 3 probably does not cross the blood
brain barrier, and there have been no reports delineating the
CNS effects of TPMPA 3 upon systemic administration.
Recently, we have synthesized a series of conformationally
restricted 3-aminocyclopentane/cyclopentene alkylphosphi-
nic acids from a structure-function study of various amino-
cyclopentane/cyclopentene phosphinic acid analogues of
GABA, and these conformationally restricted alkyl phosphinic
couple via G proteins (G ) to interact with inwardly rectifying
i/o
potassium (GIRK) and voltage-gated calcium channels, mediat-
ing slow, longer lasting synaptic inhibition by increasing potas-
3
sium and decreasing calcium conductances.
The ionotropic GABA receptors are transmembrane pro-
A
tein complexes composed of five heteropentameric sub-
units. So far, 16 human GABA receptor subunits have been
A
1
7
identified, and they have been classified into R (R -R ),
acids are highly potent and selective for GABA receptors.
1
6
C
β (β -β ), γ (γ -γ ), δ, ε, π, and θ. Although a wide range
(S)-4-ACPBPA 6 is the most potent and selective GABAC
receptor antagonist of this series. Interestingly, (S)-4-ACPBPA
1
3
1
3
of different GABA receptor combinations exist in vivo, the
A
most common is the R β γ combination, constituting
1
2 2
approximately 18% of all GABA receptors in the human
A
4
brain. The GABA receptors consist of heterodimers, which
Received Date: June 8, 2010
B
are composed of two subunits, a ligand-binding subunit
Accepted Date: October 13, 2010
Published on Web Date: October 19, 2010
3
(
GABA ), and a signal transduction subunit (GABA ).
B1 B2
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a
Scheme 1. Synthesis of Compounds 15-17
Figure 1. Structures of GABA (1), compounds active at GABA
receptors (2-7), and synthesized novel 3-AMOHP (17) and
3
-GOHP (19).
6
is a conformationally restricted analogue of the orally active
GABAB/C receptor antagonist 3-aminopropyl-n-butylphosphi-
nic acid7(CGP36742 or SGS742) (GABA , GABA , and GABA :
B
C
A
IC50 = 38, 62, and 508 μM, respectively). CGP36742 or
SGS742 reached phase II clinical trials, enhancing memory
1
8
in mildly memory-impaired subjects. However, because
CGP36742 (SGS742) is approximately equipotent on GABAB
as it is on GABA receptors, it is not clear whether the phar-
C
macological effects of CGP36742 are due to its GABA or
B
GABAC activity. In continuation of our efforts to identify
the role of GABA receptors in the CNS, we discovered that
C
the selective GABA receptor antagonists, cis- and trans-(3-
C
aminocyclopentanyl)-n-butylphosphinic acid (cis-3-ACPBPA
4
and trans-3-ACPBPA 5; Figure 1), inhibit myopia progres-
sion in chicks and facilitate learning and memory in the
Morris Water Maze task in rats.
1
9
a
4 3
Reagents and conditions: (a) (i-PrO) Si, CH CN, reflux for 2 h, 86%.
The discovery of potent and selective GABA antagonists
emphasizes some important pharmacological differences
(b) CH dCHCOOCH , NaOMe, room temperature for 24 h, 89%. (c)
C
2
3
i
CH
2
3
dCHCOOCH , NaOPr , i-PrOH, room temperature, 95%. (d) n-
BuLi, THF, 0 °C to reflux for 4 h, 86% or KOtBu, toluene, 0 °C for 5 h,
between these GABA receptor families. Thus, GABA recep-
C
8
3%. (e) 3 N HCl, i-PrOH, reflux for 12 h, 49%. (f) Tl(NO
CH Cl , room temperature for 48 h, 86%. (g) ClCOOCH CH
THF, -10 °C for 1 h; NaBH
60%. (i) 3 N HCl, reflux for 5 h, 68%. (j) DEAD, 1 M NH
PPh , THF, 12 h; 3 N HCl, reflux for 3 h, 55%.
3
)
3
3H
2
O,
N,
3
tors may be of clinical and pharmacological interest as
potential therapeutic targets for myopia, in enhancing cogni-
tion and managing memory-related disorders, and its pre-
sence in the amygdala might be an alternative target for the
2
3
2
3
, Et
3
4
0-5 °C, 4 h, 79%. (h) 3 N HCl, reflux for 8 h,
3
in benzene,
3
1
6
development of antianxiety drugs.
To date, the structural manipulations made in developing
receptor antagonists. The cyclic phosphinic acid nucleus has
not been previously used for GABA analogues, and only one
paper has described similar cyclic phosphinic acid deriva-
GABA analogues for the GABA receptor have mainly been
C
confined to the carboxylic acid end of the molecule or
restricting the conformations of the flexible GABA backbone.
As the structure-activity-relationship (SAR) profile of selec-
21
tives as glutamate receptor agonists.
The synthesis of 3-(aminomethyl)-1-oxo-1-hydroxy-phospho-
lane 17 (3-AMOHP) is depicted in Scheme 1. The intermediate
isopropoxy-1-oxophosphorinan-4-one 12 was prepared in five
steps from water-free hypophosphoric acid, with few mod-
tive GABA receptor ligands is limited, there is a need to
C
develop more structurally diverse GABA receptor ligands to
C
understand the physiological role of these receptors. During
the course of our ongoing research, we envisioned a novel
2
2
ifications as previously described by Verkade et al. Hypo-
phosphoric acid was treated with commercially available
tetraisopropyl orthosilicate to afford isopropyl phosphinate
8, which was treated with methyl acrylate to provide diester
9. The diester 9 was treated with methyl acrylate in iso-
propanol to afford triester 10, which was cyclized in the
presence of base to afford compound 11. The selective hy-
drolysis of compound 11 is a key step to afford intermediate
template for the GABA receptor by modifying the terminal
C
nitrogen to incorporate a guanidino functional group, which
2
0
is known to act at GABA receptors along with restraining
the phosphinic acid moiety (bioisostere of the carboxylic
acid). Therefore, in the present study, we report the design,
synthesis, and pharmacological evaluation of synthetically
challenging cyclic phosphinic acid analogues as GABAC
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isopropoxy-1-oxophosphorinan-4-one 12. The selectivity re-
lies on the difference in reactivity of the carboxylic and
phosphinic esters. We investigated several different reaction
conditions (such as different concentrations of HCl in iso-
propanol at room/elevated temperature), and the best con-
dition, which gave a reasonable yield of the intermediate 12,
was the treatment of the compound 11 with 3 N hydrochloric
acid in the presence of isopropanol.
six-membered ketone. The carboxylic acid 13 was re-
duced to primary alcohol 14 using NaBH through in situ
4
mixed carbonic-carboxylic acid anhydride. Finally, the
amine was generated via a one pot Mitsunobu-Staudinger
reaction, followed by phosphinate ester hydrolysis using
aqueous HCl and the crude product purified via ion-exchange
chromatography and recrystallization to give the free
amine 17 (Scheme 1). Compounds 15 and 16 were pre-
pared by hydrolysis of corresponding phosphinate esters
using aqueous HCl.
The syntheses of 3-(amino)-1-oxo-1-hydroxy-phospho-
lane (3-AOHP) 18 and 3-(guanido)-1-oxo-1-hydroxy-phos-
pholane (3-GOHP) 19 are depicted in Scheme 2. Modified
Curtius rearrangement of the acid 13 and hydrolysis of the
intermediate isocyanates with aqueous HCl afforded the
amine 18. Compound 19 was prepared by guanylation of
amine 18 using formamidinesulfinic acid in the presence of
a base.
The phospholane-1-oxide carboxylic acid 13 was synthe-
sized from keto phosphinane-1-oxide 12 via ring contrac-
2
3
tion along with oxidation reaction in one step. This
observation may be of synthetic utility for five-membered
heterocycle formation; as to the authors knowledge, it is
the first demonstration of direct one-step access to hetero-
cyclic five-membered carboxylic acid from heterocyclic
a
Scheme 2. Synthesis of Compounds 18 and 19
The functional characterization of the cyclic phosphinic
acids at GABA receptors was performed using two-electrode
voltage clamp on recombinant human GABA receptors ex-
1
7,24
pressed in Xenopus oocytes.
15-19) were evaluated for activity alone and in the presence
The cyclic phosphinic acids
(
of GABA on GABA (R β γ ), GABA (1b/2), and GABA (F
A
1
2
2L
B
C
1
and F ) receptors to determine whether they behave as
2
agonists, antagonists, or modulators. It has previously been
observed that orientations of the acid, backbone, and amine
group are important for antagonist activity at GABA receptors,
but the distance between acid-amine counterparts and the
use of alkyl phosphinic acids as a bioisostere of a carboxylic
acid are also an important criterion to develop selective
17
GABA antagonists.
C
As shown in Table 1, we have examined the effects of cyclic
a
Reagents and conditions: (a) ClCOOCH
2 3 3
CH , Et N, acetone, -10 °C
phosphinic acids (15-19) on GABA , GABA , and GABA recep-
A
B
C
for 1 h. (b) NaN
3
, H O, 2 h. (c) Toluene, reflux for 2 h. (d) 3 N HCl, reflux
2
tors. Compounds 15 and 16, which lack the terminal nitrogen
showed no effects at 100 μM on all three GABA receptors.
2
for 3 h, 48%. (e) Formamidinesulfinic acid, NaOH, H O, room tempera-
ture for 12 h, 76%.
Table 1. Pharmacological Data
human GABA
C
receptors
(μM)
IC50 (95% CI)/K
B
1 2 A
human GABAB (1b/2) receptors human R β γ2L GABA receptors
compd
F
1
F
2
EC50 (μM) or % inhibition
K
B
(μM) or % inhibition
a
a
TPMPA (3)
IC50 =2.22 (1.32-6.09) μM
IC50 =22.09
18.87-25.86) μM
K = 14.9 μM
B
EC50 = ∼500 μM
B
K = 320 μM
(
a
b
K
K
B
=2.1 μM
c
c,d
c,e
(
S)-4-ACPBPA (6)
B
=4.97 μM
22.5 ( 1.9%
24.2 ( 1.7%
IC50 =508 μM
f
f
f
CGP36742 (7)
IC50 =62 μM
IC50 =38 μM
1
1
1
5
6
7
inactive at 100 μM
inactive at 100 μM
inactive at 100 μM
inactive at 100 μM
inactive at 100 μM
inactive at 600 μM
inactive at 100 μM
g
IC50 =19.91 (16.79-23.60) μM
IC50 =57.13
54.92-63.39) μM
weak agonist
(
h
1
1
8
9
inactive at 600 μM
9.76 ( 4.6%
inactive at 600 μM
e
IC50 =29.74 (26.64-35.42) μM
IC50 =51.31
(47.30-55.40) μM
inactive at 600 μM
29.21 ( 2.3%
i
K
B
=10 ( 1.6 μM
a
b
c
d
Data from ref 12. Data from ref 24. Data from ref 17. Percentage inhibition by 300 μM compound of the current produced bya submaximal does
e
of GABA (3 μM, EC50). Data are the means ( SEMs (n = 3-5 oocytes). Percentage inhibition by 600 μM compound of the current produced by
f
g
a submaximal does of GABA (30 μM, EC50). Data are the means ( SEMs (n = 3 oocytes). Data from ref 18. Figure 2A showing the weak agonist
h
effects of 3-AMOHP 17. Percentage inhibition by 600 μM compound of the current produced by a submaximal does of GABA (3 μM, EC50). Data are the
i
means ( SEMs (n = 3 oocytes). The K
B
value is the mean ( SEM.
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Figure 2. (A) Samplecurrent traceshowing the effectsof3-AMOHP17onhumanGABAB(1b/2) receptors coexpressedwithGIRK1/4 channelsin
þ
Xenopus oocytes using 45 mM K buffer (forward hatched bar). 3-AMOHP 17 had no effect at 10 μM (black bar) but activated GABA
B
receptors
at100(green bar) and 600 μM (purplebar) ina concentration-dependent manner, indicatingweakagonist effects atthisreceptor. (B) Inhibitory
concentration-response curvesfor TPMPA 3 (red dot, n = 4), 3-AMOHP 17(green square, n = 3), and 3-GOHP 19(blue triangle, n = 4) against
1
GABA (1 μM) at human F GABA receptors expressed in Xenopus oocytes. Data are the means ( SEMs (n = 3-4 oocytes). (C) Inhibitory
concentration-response curvesfor TPMPA 3 (red dot, n = 3), 3-AMOHP 17(green square, n = 4), and 3-GOHP 19(blue triangle, n = 4) against
2
GABA (1 μM) at human F GABA receptors expressed in Xenopus oocytes. Data are the means ( SEMs (n = 3-4 oocytes). (D)
Concentration-response curves of GABA alone (red dot, n = 3) and GABA in the presence of 10 (green triangle, n = 4), 30 (blue square,
n = 3), and 100 μM ((, n = 4)19 at human F1 GABAC receptors expressed in Xenopus oocytes. Data are the means ( SEMs (n = 3-4 oocytes).
It proved that both the acid and the amino counterparts are
important for the ligand's affinity at these receptors. 3-AMOHP
tolerated at the GABA receptor ligand-binding site. 3-AOHP
C
18 was inactive at all three GABA receptors, which indicates
that the distance between the acidic group and the terminal
nitrogen of GABA receptor ligands appears to be important for
ligand affinity at these receptors. Figure 2B shows the inhibi-
tory concentration-response curves for the active analogues
(TPMPA 3, 3-AMOHP 17, and 3-GOHP 19) against GABA
(1 μM) at F GABA receptors. The active compounds were fur-
1
7 was found to be a potent antagonist (IC50 = 19.91 μM) at F1
GABAC receptors, inactive (at 600 μM) at R β γ GABAA
1
2 2L
receptors, and a weak agonist at GABAB(1b/2) receptors. Figure
A shows the effect of 3-AMOHP 17 on GABAB(1b/2) receptors
2
expressed in Xenopus oocytes. 3-AMOHP 17 shows activation
itself at 100 (33.22 ( 4.65%) and 600 μM (45.17 ( 5.23%),
indicating its weak agonist nature at GABAB(1b/2) receptors.
1
C
ther tested at human F GABA receptors. Figure 2C shows the
2
C
3-GOHP 19 was developed based on the observed activities
inhibitory concentration-response curves for the TPMPA 3
(IC =22.09 μM),3-AMOHP17 (IC =57.13 μM),and3-GOHP
of 4-guanidinobutanoic acid 2 (4-GBA), which is an antagonist
50
50
at GABA and GABA receptors with no effects on GABA
19 (IC50 =51.31μM) against GABA (1μM) at F GABA receptors.
A
C
B
2 C
20
receptors. ω-Guanidino acids are known to act like GABA at
GABA receptors, indicating that guanidino acids behave as
though the guanidino group is equivalent to the amino func-
Both compounds (17 and 19) are moderately potent antagonists
at F GABA receptors. In addition, 3-GOHP 19 caused a parallel
2
C
rightward shift of the GABA concentration-response curves in
the presence of three antagonist concentrations, indicating its
20
tionality with a more basic nature. 3-GOHP 19 is a potent
and selective antagonist (K = 10.0 ( 1.6 μM) at the F GABA
competitive nature (Figure 2D; K = 10.0 ( 1.6 μM).
B
1
C
B
receptor. 3-GOHP 19 has reduced activity (29% inhibition
at 600 μM) at R β γ GABA receptors and was inactive (at
To delineate the key interactions responsible for differ-
ences in binding affinity, the structures of TPMPA 3,
(S)-4-ACPBPA 6, and each stereoisomer of 3-AMOHP 17,
3-AOHP 18, and 3-GOHP 19 were flexibly docked into the
1
2
2L
A
600 μM) at GABAB(1b/2) receptors, indicating that substituting
the amine functionality with a guanidino moiety is well
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Figure 3. View of the F
1
GABA
C
ligand-binding site with predicted binding modes. (A)TPMPA 3 (green carbons) and (S)-4-ACPBPA 6 (yellow
carbons). (B) Stereoisomer of 3-AMOHP 17: (R)-3-AMOHP (green carbons) and (S)-3-AMOHP (yellow carbons). (C) Stereoisomer of 3-GOHP
1
9: (R)-3-GOHP (green carbons) and (S)-3-GOHP (yellow carbons). (D) Stereoisomer of 3-AOHP 18: (R)-3-AOHP (green carbons) and (S)-3-
AOHP (yellow carbons).
ligand-binding site of a F GABA homology model (see the
Supporting Information for details). Figures 3B,C shows the
S- and R-stereoisomers of both 3-AMOHP 17 and 3-GOHP
region for further lead optimization. In conclusion, the
synthesis of novel cyclic phosphinic acid template has been
developed. The activity of these compounds has been
investigated at the three major GABA receptor families,
and 3-AMOHP 17 and 3-GOHP 19 (ω-guanidino acid) are
1
C
1
9. These compounds are predicted to bind similarly to
TPMPA 3 and (S)-4-ACPBPA 6 (Figure 3A). The binding
affinity is largely ascribed to various electrostatic interac-
discovered as potent and selective GABA receptor antago-
nists. This is first demonstration of a ω-guanidino acid as a
C
25-28
tions,
phosphinic acid and the Arg104, (ii) a salt bridge interac-
including (i) a salt bridge interaction between the
2
5
selective GABA receptor antagonist. These results offer new
C
2
5
tion between the basic amine/guanidino and the Glu196,
knowledge of the architecture of GABA receptor ligand's for
C
(
iii) hydrogen bond contacts to Ser168 and Thr244 and to
studies regarding the binding site and receptor flexibility. In
future studies, it might be useful to generate complete SARs
of this novel template for developing into more potent and
2
6,27
the backbone carbonyl of Tyr198,
attraction between the basic amine and the Tyr247,
an experimentally determined interaction. While simi-
lar binding energies are predicted for the structures of
3
and (iv) a cation
π
3
3 3
2
8
selective GABA receptor antagonists.
C
SUPPORTING INFORMATION AVAILABLE Synthetic ex-
perimental procedures, analytical and spectral characterization
data of all synthesized compounds including elemental analyses,
and details of molecular modeling and pharmacology. This material
is available free of charge via the Internet at http://pubs.acs.org.
-AMOHP 17 and 3-GOHP 19 (see the Supporting In-
formation), the larger guanidino group of 3-GOHP 19 incurs
a slightly higher ligand strain penalty (∼3-4 kcal/mol) than
3
-AMOHP 17, which may account for it is slightly decreased
activity on F GABA activity. The complete inactivity of
3
neither the S- nor the R-stereoisomer can optimally span the
width of the binding site (Figure 3D); therefore, they are
unable to interact with Arg104 and Glu196 simultaneously,
amino acids known to be important for GABA binding.
1
C
-AOHP 18 on F GABA is most likely due to the fact that
1 C
AUTHOR INFORMATION
Corresponding Author: *Tel: þ61-2-93518584. E-mail: maryc@
pharm.usyd.edu.au.
Funding Sources: N.G. acknowledges support from an Ende-
vour International Postgraduate Research Scholarship (EIPRS) and
the John Lamberton Scholarship.
Furthermore, they cannot establish a favorable cation
π
3
3 3
attraction with Tyr247. Among all ligands docked, the
largest difference is seen with (S)-4-ACPBPA 6, which ad-
ditionally inserts a butyl chain into a hydrophobic pocket
enclosed by Tyr198, Leu166, and Arg158 (CR, Cβ, Cγ, and
Cδ atoms) (Figure 3A). This moiety potentially liberates
ACKNOWLEDGMENT We are thankful to Bruce Tattam and Dr.
Keith Fischer for technical assistance with mass spectrometry
measurements. We are also thankful to Hye-Lim Kim for technical
assistance with the two-electrode voltage clamp method.
2
9
thermodynamically unfavorable waters and highlights a
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DOI: 10.1021/ml1001344 |ACS Med. Chem. Lett. 2011, 2, 11–16