An in vitro investigation into conformational aspects of gabapentin

Article abstract of DOI:10.1016/S0968-0896(99)00023-1

Conformational analysis of constrained cyclohexane systems was pioneered fifty years ago by Barton and Hassel. We now report an investigation based on a conformational analysis of a number of novel cyclohexane based Gabapentin analogues coupled with their in vitro evaluation at the Gabapentin binding site. These data are used to propose a possible binding conformation for Gabapentin. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00023-1

Bioorganic & Medicinal Chemistry 7 (1999) 715±721
An In Vitro Investigation into Conformational
Aspects of Gabapentin
Justin S. Bryans,a,* David C. Horwell,a Giles S. Ratcli€e,a Jean-Marie Receveura
and J. Ronald Rubinb
aParke Davis Neuroscience Research Centre, Forvie Site, Robinson Way, Cambridge CB2 2QB, UK
bParke Davis, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 88105, USA
Received 25 June 1998; accepted 21 August 1998
AbstractÐConformational analysis of constrained cyclohexane systems was pioneered ®fty years ago by Barton and Hassel. We
now report an investigation based on a conformational analysis of a number of novel cyclohexane based Gabapentin analogues
coupled with their in vitro evaluation at the Gabapentin binding site. These data are used to propose a possible binding con-
formation for Gabapentin. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
of protein binding in vivo.16 Recently, it has been shown
that Gabapentin binds with high anity to a novel
binding site on the a2d subunit of a calcium channel.17±19
It is currently proposed that Gabapentin exerts its anti-
convulsant and anti-nociceptive actions via interaction
with this site, and it is this interaction that the work
described here is centred on.
Conformational analysis of cyclic systems was ®rst
brought to light ®fty years ago in the pioneering work
of Barton and Hassel.1±3 The principles they described
have since been applied to many stereochemical aspects
of cyclohexane based systems, including addition of
nucleophiles to conformationally constrained cyclohex-
anones4±6 and cyclohexylidenecyanoacetates.7 We have
now applied these and other principles to undertake an
investigation into the preferred binding conformation of
the cyclohexane derivative Gabapentin (Neurontin1) (1)
for optimal interaction with its binding site.
Results and Discussion
The two lowest energy conformations of Gabapentin
contain the cyclohexane ring in the chair conformation
and have the aminomethyl moiety either axial (1a) or
equatorial (1b). We have recently proposed that, for
optimum binding, the aminomethyl should be in the
equatorial frame relative to the cyclohexane system as in
conformer 1b.20 In order to examine this more rigor-
ously we have investigated the conformations of a
number of analogues utilising low temperature 1H
NMR techniques.
Gabapentin (1) has been introduced as an anti-
convulsant agent that is useful as add on therapy in the
treatment of epileptic seizures.8 It has also recently been
shown to be a potential treatment for neurogenic pain.9±11
Gabapentin was originally designed as a lipophilic g-
amino butyric acid (GABA) analogue,12 but has subse-
quently been shown not to interact with any of the
enzymes on the GABA metabolic pathway, nor does it
interact directly with the GABAA or GABAB recep-
tors.13 However, it is able to eciently cross the blood
brain barrier via an L-system amino acid transporter.14
Gabapentin shows few, if any, toxic side e€ects at clini-
cally relevant doses.15 It does, however, possess a rela-
tively short half life, being excreted unchanged, possibly
due to its very high water solubility and apparent lack
We synthesised the cis and trans isomers of (3R)-(1-
aminomethyl-3-methylcyclohexyl)-acetic acid 2 and 3,
respectively, by the routes outlined previously,20,21 the
key steps being (Scheme 1) the addition of nitromethane
to the a,b-unsaturated ester (4) and the addition of cy-
anide to the Knoevenagel adduct (6).
It is interesting to note that the direction of addition of
the two nucleophiles occur from opposite faces with the
nitromethane approaching from the equatorial direction
and cyanide approaching from the axial direction,
almost exclusively in both cases, as shown by NOE dif-
Key words: Anticonvulsants; molecular modelling; NMR; X-ray crys-
tal structures.
*Corresponding author. Tel.: +44 (0)1223-210-929; fax: +44 (0)1223-
416-712; e-mail: justin.bryans@camb.wl.com
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00023-1

716
J. S. Bryans et al. / Bioorg. Med. Chem. 7 (1999) 715±721
Scheme 1. (i) MeNO2, THF, Bu4N+F , 70ꢀC, 18 h (65%); (ii) KCN,
EtOH, H2O, re¯ux, 18 h (70%).
exist so the cyanide simply attacks from the face giving
rise to the more thermodynamically stable product. The
intermediate 10, when compared to 11, has a smaller
1,3-diaxial interaction between the two axial hydrogens
on C-3 and C-5 and the axial moiety on C-1. Thus,
intermediate 10 is the more thermodynamically stable
intermediate so the reaction proceeds through this
pathway.
Gabapentin was examined by 1H NMR in deuter-
omethanol at room temperature when only a single set
of signals is observed owing to the rapid ring ¯ipping at
this temperature. On cooling to 80 ꢀC two sets of exo-
cyclic methylene signals were observed in a ratio of 1:2.
These signals corresponded to the two conformers 1a
and 1b, respectively and were assigned as such by com-
parison of the relative shifts of the two pairs of exocyclic
methylene moieties with the corresponding signals from
conformationally restricted analogues 2 and 3. In con-
trast, both 2 and 3 were shown to exist in single detect-
able conformations (>99%) at 80 ꢀC, compound 2
being e€ectively constrained in the conformation with
the aminomethyl in the equatorial frame and compound
3 constrained with the aminomethyl axial. Compounds
2 and 3 were examined for binding at the Gabapentin
binding site and the results are shown in Table 1.
Although both 2 and 3 are expected to undergo ring
¯ipping at room temperature the proportion of any
other conformers will be small (<1%) thus making it
unlikely that any of these are contributing to the bind-
ing anity observed. The data in Table 1, coupled with
the evidence of only a single conformer being accessible
at room temperature for compounds 2 and 3, con®rm
that the binding conformation of Gabapentin is that
with the aminomethyl in the equatorial frame.
ference experiments carried out on the ®nal compounds
2 and 3. The outcome of the nitromethane addition can
be rationalised via the proposed six membered transi-
tion states 8 and 9 incorporating the nitromethane
anion and the tetrabutylammonium cation.7 As can be
seen, the 1,3 diaxial interactions between the two axial
hydrogens on C-3 and C-5 and the axial moiety on C-1
are much more unfavourable for axial attack of nitro-
methane (transition state 9) so driving the nitromethane
to approach from the equatorial frame.
For the reaction involving potassium cyanide, the
potassium cation and cyanide anion are almost com-
pletely dissociated in the ethanol solvent.7 In this case it
should also be remembered that the initial product of
the addition is the cyanoester 10 or 11 that subsequently
undergoes hydrolysis and decarboxylation to give the
product. Owing to the dissociation of the potassium and
cyanide ions a six membered transition state does not
Having de®ned the probable conformation of the cy-
clohexane ring the investigation was extended to exam-
ine the GABA portion of Gabapentin. Here there are a
number of low energy conformations accessible. Com-
puter models were built and energy minimised using
Sybyl 6.3.22 The model for Gabapentin was built with
the cyclohexane ring in the chair conformation and with
the aminomethyl group equatorial. The conformations

J. S. Bryans et al. / Bioorg. Med. Chem. 7 (1999) 715±721
717
of the GABA subunit were then enumerated using a
grid search, using 15ꢀ increments about bonds a,b (see
Fig. 1; the torsion angles were de®ned by the following
atoms: a (1,2,3,4), b (2,3,4,5)); energy minimisation of
the other bonds then gives the relative energy of each
conformer. The geometry optimisation was e€ected by
minimisation of the molecular mechanics energy (Tripos
force ®eld, with Gasteiger±Marsili charges using a dis-
tance dependent dielectric constant) by MAXIMIN-II.
The geometry optimisation was also used during and
after the grid search procedure and energy minimisation
was terminated when the rms energy gradient fell below
0.01 kCal/mol/A. Six conformations from the low
energy regions were identi®ed and further minimised.
The geometry and energy of these conformers are
shown in Table 2.
Conformations 1 and 5 are close to being mirror images
and so constitute one pair and conformations 2 and 4
are also close to mirror images so constituting a second
pair. In order to further investigate the pair of con-
formers 2 and 4 a more rigid Gabapentin analogue (12)
was designed. The (S)-enantiomer 12a closely mimics
conformer 2 (Figure 2(a)), whereas the (R)-enantiomer
12b closely mimics the conformer 4 (Figure 2(b)). The
models were overlaid by the method of least squares
over three pairs of atoms. The racemate 12 was synthe-
sised as its hydrochloride salt by the route outlined in
Scheme 2. The two enantiomers could be prepared
individually via benzyloxycarbonyl protection (19) of
the racemic amino acid followed by amide formation
It has been found that a number of lipophilic a-amino
acids also bind to the Gabapentin binding site. Thus it is
proposed that the amine and acid moieties of Gaba-
pentin should be close enough to each other that they
can mimic an a-amino acid; this precludes conforma-
tions 3 and 6 in Table 2. Thus four conformations are
left for consideration, which fall into two pairs.
Table 1. a2d subunit binding site anities for 3-methyl Gabapentin
analogues
Compound
Structure
IC50(nM)a
Gabapentin (1)
140(1)
2
3
42(6)
>1000
aIC50 is the concentration (nM) producing half-maximal inhibition of
the speci®c binding of [3H]-Gabapentin to Gabapentin binding sites
located on the a2d subunit of a calcium channel. Values shown repre-
sent the geometric mean of at least three experiments with the stan-
dard error of the mean in parentheses.
Figure 2. (a) Overlay of Gabapentin conformer 2 (in green) with 12a;
(b) Overlay of Gabapentin conformer 4 (in green) with 12b.
Figure 1. Torsion angles a and b used for the grid search of the
GABA subunit of Gabapentin.

718
J. S. Bryans et al. / Bioorg. Med. Chem. 7 (1999) 715±721
with (R)-(+)-1-(2-Naphthyl)ethylamine to give the two
diastereoisomers 20a and 20b, which were separable by
¯ash chromatography. To ascertain the absolute
stereochemistry of 20a and 20b, one of the samples (20a)
was prepared for X-ray analysis. Crystal structure
determination (Fig. 3) showed that 20a had the absolute
con®guration of (R) at the stereocentre adjacent to the
naphthalene ring, as expected, and (S) for the centre in
the ®ve membered ring. By elimination, the isomer 20b
must have absolute con®gurations of (R) and (R),
respectively. Hydrolysis of the pure diastereoisomers
gave rise to the individual enantiomers 12a and 12b with
(S) and (R) con®gurations, respectively.
The enantiomers 12a and 12b were tested for binding at
the Gabapentin binding site and gave IC50 values of
Table 2. Conformations of the GABA subunit of Gabapentin (1)
Conformation
Torsion angles a,b
Molecular mechanics
energy kCal/mol
Distance
N to CO2H A
1
2
3
4
5
6
57.2,78.0
44.6,54.3
178.3,60.6
53.4, 55.5
69.6, 60.4
170, 54.8
3.84
2.97
5.80
4.62
5.65
5.33
3.03
3.23
4.43
3.39
2.91
4.40
Scheme 2. (i) HCl.BnNHCH2CO2H, Et3N, HCHO, PhH, re¯ux (82%); (ii) 6 N HCl re¯ux (94%); (iii) MeOH, HCl, re¯ux (65%); (iv) Pd(OH)2/C,
H2, MeOH (97%); (v) BnOCOCl, Py, CH2Cl2, (88%); (vi) oxane/aq NaOH (89%); (vii) CH2Cl2, (COCl)2, HCONMe2 then (R)-(+)-1-(2-napthyl)-
ethylamine followed by ¯ash chromatography, 20a: 43%, and 20b: 39%; (viii) 6 N HCl, THF re¯ux (73%); (ix) 6 N HCl, THF re¯ux (78%).

J. S. Bryans et al. / Bioorg. Med. Chem. 7 (1999) 715±721
719
matography was Merck no. 9385 (230±400 mesh), and
reverse phase silica gel used was Lichroprep RP-18
(230±400 mesh); both were supplied by E. Merck, A.G.,
Darmstadt, Germany. Anhydrous solvents were pur-
chased in Sureseal2 bottles from Fluka Chemicals Ltd.,
Glossop, UK. For the X-ray data a colourless rod
crystal of (20a) was mounted on a glass ®bre with its
long axis roughly parallel to the phi axis of the goni-
ometer. Preliminary examination and data collection
were performed with Cu Ka radiation (l=1.54184 A)
on an Enraf±Nonius CAD4 computer controlled kappa
axis di€ractometer equipped with a graphite crystal,
incident beam monochromator. Cell constants and an
orientation matrix for data collection were obtained
from least squares re®nement, using the setting angles of
25 re¯ections in the range 23ꢀ<y<43ꢀ, measured by the
computer controlled diagonal slit method of centring.
The data were collected at 23 ꢀC using the omega scan
technique. A total of 3394 re¯ections were collected, of
which 3364 were unique and not systematically absent.
The structure was solved by direct methods. Using 277
re¯ections (minimum E of 1.66) and 3293 relationships,
a total of 25 phase sets were produced. A total of 38
atoms were located from an E-map prepared from the
phase set with probability statistics. The remaining
atoms were located in succeeding di€erence Fourier
transform syntheses.
Figure 3. X-ray crystal structure of 20a.
>10 mM and 120 nM, respectively. These data are con-
sistent with the binding conformation of Gabapentin
being close to conformer 4, for good interaction with its
binding site on the a2d subunit of a calcium channel.
2-Benzyl-2-aza-spiro[4.5]decane-4-carboxylic acid methyl
ester (16). A solution of (13) (4 g; 20.70 mmol), N-Ben-
zylglycine hydrochloride (10.4 g; 51.57 mmol), Triethy-
lamine (7.2 mL; 51.65 mmol) and Paraformaldehyde
(5.2 g; 173.30 mmol) in Benzene (120 mL:) was re¯uxed
for 2 h using a Dean±Stark apparatus. After cooling, the
reaction mixture was diluted with Toluene (200 mL) and
washed with brine. The aqueous phase was extracted
with Toluene (3Â30 mL). The organic extracts were
combined, dried over MgSO4 and concentrated in
vacuo. The crude oil was puri®ed over silica-gel chro-
matography in EtOAc/Heptane (1/3) to give a yellow
oil, which was diluted in ether (30 mL) and extracted
with 3 N HCl (3Â25 mL). The aqueous phase was
washed with ether (2Â30 mL) and was concentrated
under vacuum to give 14 as a white powder (6.20 g;
17.08 mmol), which was used without any further pur-
i®cation. A solution of 14 (6.2 g; 17.08 mmol) in 6 N
HCl (120 mL) was re¯uxed overnight. Evaporating the
solvent in vacuo gave 5 g (16.13 mmol; 77% from 13) of
15 as a pale-yellow solid, which was immediately ester-
i®ed. Acetyl chloride (5 mL; 70.32 mmol) was slowly
added to methanol (100 mL), at 0 ꢀC, under an argon
atmosphere. After stirring for 10 min, this solution was
transferred to a ¯ask containing 15 (5 g; 16.13 mmol),
under an argon atmosphere. The reaction mixture was
then stirred at 95 ꢀC for 3 h. After cooling, the methanol
was removed in vacuo. The residue was basi®ed with
sat. aq Na2CO3 and was extracted with ether
(3Â30 mL). The organic phases were combined, dried
over MgSO4 and concentrated to give 3 g (10.44 mmol;
Conclusion
We have demonstrated, utilising low temperature 1H
NMR techniques of conformationally constrained
Gabapentin analogues, that the probable binding con-
formation of Gabapentin is that with the aminomethyl
moiety in the equatorial frame in relation to the cyclo-
hexane ring. The low temperature 1H NMR of sub-
stituted Gabapentin analogues detected only a single
conformation in each case, showing other conforma-
tions are unlikely to make a contribution to the binding
anity observed. Moreover, a novel Gabapentin analo-
gue with a constrained GABA portion has been used to
probe the binding conformation of the GABA moiety of
Gabapentin during its interaction with the binding site.
Experimental
Melting points were determined with a Mettler FP80 or
a Reichert Thermovar hot-stage apparatus. Proton
NMR spectra were recorded on a Varian Unity +400
spectrometer; chemical shifts are recorded in ppm
down®eld from tetramethylsilane. IR spectra were
recorded on a Perkin±Elmer System 2000 Fourier
transform spectrophotometer. Mass spectra were recor-
ded with a Finnigan MAT TSQ70 or Fisons VG Trio-
2A instrument. Elemental analyses are within ‹0.4% of
theoretical values and were determined by Medac Ltd.,
Uxbridge, UK. Normal phase silica gel used for chro-
1
50% from 13) of 16 as a pale-yellow liquid. H NMR
(CDCl3, 400 MHz): d 1.0±1.7 (m, 10H), 2.25 (d, 1H),
2.65±2.9 (m, 4H), 3.6 ([AB]q, 2H), 3.65 (s, 3H, OCH3),
7.3 (m, 5H, Ph); MS (ES+) m/e: 288 ([MH]+, 100%).

720
J. S. Bryans et al. / Bioorg. Med. Chem. 7 (1999) 715±721
2-Aza-spiro[4.5]decane-2,4-dicarboxylic acid 2-benzyl ester
4-methyl ester (18). A solution of 16 (3 g; 10.44 mmol)
and 10% Pd(OH)2/C (0.60 g; 20%w/w) in methanol
(50 mL) was stirred for 24 h at 40 ꢀC under an atmo-
sphere of dry hydrogen gas. The catalyst was ®ltered o€
through a Celite pad and the ®ltrate was concentrated in
vacuo to give 2 g (10.14 mmol; 97%) of 17 as a colour-
less oil, which was used without any further puri®ca-
tion. To a solution of 17 (2 g; 10.14 mmol) in dry
Dichloromethane (100 mL) was successively added, at
0 ꢀC, under an argon atmosphere, pyridine (2.04 mL;
25.35 mmol) and benzylchloroformate (2.89 mL;
20.24 mmol). The reaction mixture was then allowed to
stir at room temperature for 2 days. The reaction mix-
ture was washed (2Â50 mL) with 1 N HCl, dried over
MgSO4 and concentrated in vacuo. The crude oil was
puri®ed by silica-gel ¯ash chromatography in ether/
heptane (1/1) to give 2.97 g (8.96 mmol; 88%) of 18 as a
(20a): 1.2±1.65 (m, 13H), 2.4 (m, 1H), 3.35 (d, 1H), 3.5±
3.8 (m, 3H), 5.1 (m, 2H), 5.3 (m, 1H), 5.7 (t, 1H), 7.3±
7.8 (m, 12H). (20b): 1.2±1.65 (m, 13H), 2.4 (m, 1H), 3.25
(d, 1H), 3.5±3.8 (m, 3H), 5.1 (m, 2H), 5.3 (m, 1H), 5.7 (t,
1H), 7.3±7.8 (m, 12H). MS (ES+) m/e: (20a) : 471 ([MH ]+,
100%); (20b): 471 ([MH]+, 100%).
(S)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride
(12a). To a solution of 20a (770 mg; 1.64 mmol) in
THF (5 mL) was added 6 N aq HCl (40 mL). The reac-
tion mixture was stirred under re¯ux overnight. After
cooling, the reaction mixture was washed with EtOAc
(2Â20 mL). The phases were separated and the aqueous
phase was concentrated to dryness under vacuum. The
crude residue was dissolved in 6 N aqueous HCl (40 mL)
and the reaction mixture was stirred under re¯ux for
60 h. After cooling, the reaction mixture was washed
with EtOAc (2Â20 mL). The phases were separated and
the aqueous phase was concentrated to dryness to leave
a solid, which was dissolved in water. Removing water
under vacuum led to 12a as a white powder (263 mg;
1
colourless oil. H NMR (CDCl3, 400 MHz) d: 1.15±1.7
(m, 10H), 2.8 (m, 1H), 3.3 (m, 1H), 3.45±3.8 (m, 6H),
5.15 ([AB]q, 2H, PhCH2), 7.3 (m, 5H, Ph). MS (ES+)
m/e: 332 ([MH]+, 100%).
1
1.20 mmol; 73%). H NMR (CDCl3, 400 MHz) d: 1.2±
1.8 (m, 10H), 3.1 (t, 1H), 3.4 ([AB]q, 2H), 3.7 (m, 2H).
MS (ES+) m/e: 184 ([MH]+, 100%). Microanalysis cal-
culated for C10H17NO2.HCl: C 54.67% H 8.26% Cl
16.14% N 6.37%. Found: C 54.51% H 8.46% Cl
15.96% N 6.22%.
2-Aza-spiro[4.5]decane-2,4-dicarboxylic acid 2-benzyl ester
(19). To a solution of 18 (300 mg; 0.9 mmol) in a mix-
ture dioxane/water (6 mL; 9/1) was added a 2 M solu-
tion of NaOH (0.90 mL; 1.8 mmol). The reaction
mixture was stirred at 35 ꢀC for 6 h. Solvents were
removed in vacuo. The residue was diluted in water
(15 mL) and was washed with diethyl ether (3Â10 mL).
The aqueous phase was acidi®ed with 2 N HCl and was
extracted with ethyl acetate (3Â15 mL). The ethyl ace-
tate extracts were combined, dried over MgSO4 and
concentrated to give 254 mg (0.8 mmol, 89%) of 19 as a
colourless gum. 1H NMR (CDCl3, 400 MHz) d: 1.2±
1.75 (m, 10H), 2.8 (m, 1H), 3.3 (m, 1H), 3.5 to 3.8 (m,
3H), 5.1 (ABq, 2H), 7.3 (m, 5H). MS (ES+) m/e: 318
([MH]+, 100%).
(R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride
(12b). Compound 20b (553 mg; 1.17 mmol) was con-
verted to 200 mg (0.91 mmol; 78%) of 12b by the same
1
procedure for 20a to 12a. H NMR (CDCl3, 400 MHz)
d: 1.2±1.8 (m, 10H), 3.1 (t, 1H), 3.4 ([AB]q, 2H), 3.7 (m,
2H). MS (ES+) m/e: 184 ([MH]+, 100%). Micro-
analysis calcd for C10H17NO2.HCl: C 54.67% H 8.26%
Cl 16.14% N 6.37%. Found: C 54.48% H 8.42% Cl
15.99% N 6.18%.
(4S,10R)-4-(10 -Naphthalen-2-yl-ethylcarbamoyl)-2-aza-
spiro[4.5]decane-2-carboxylic acid benzyl ester (20a) and
(4R,10R)-4-(1(-naphthalen-2-yl-ethylcarbamoyl)-2-aza-
spiro[4.5]decane-2-carboxylic acid benzyl ester (20b). To
a cooled (0 ꢀC) solution of 19 (1.71 g; 5.38 mmol) in dry
dichloromethane (35 mL) were successively added,
under an argon atmosphere, oxalyl chloride (0.56 mL,
6.42 mmol) and dimethylformamide (20 mL; 0.26 mmol).
The reaction mixture was stirred at 0 ꢀC for 30 min and
then was allowed to stir at room temperature for 2 h.
The solvent was removed in vacuo and the residue was
diluted in dry dichloromethane (35 mL). This solution
was then added to a solution of (R)-(+)-1-(2-naphthyl)
ethylamine (1.10 g; 6.42 mmol) and triethylamine
(0.90 mL, 6.42 mmol) in dry dichloromethane (50 mL),
under an argon atmosphere. The reaction mixture was
stirred at room temperature overnight. 2 N HCl (30 mL)
was added and the organic and aqueous phases were
separated. The organic phase was washed with water
(30 mL), dried over MgSO4 and concentrated to give a
pale-yellow oil, which was puri®ed over silica-gel chro-
matography in EtOAc/heptane (1/1) to give 1.1 g
(2.34 mmol; 43%) of 20a and 1.0 g (2.12 mmol; 39%) of
20b as white solids. 1H NMR (CDCl3, 400 MHz) d:
Acknowledgements
We would like to thank Jane McGu€og for HPLC
analysis and mass spectral data, Lindsey Terry for
NMR analysis, Jack Bikker for X-ray data visualisa-
tion, and Nicolas Gee, Visaka Dissanayake and Sandra
Du€y for in vitro assays.
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22. Sybyl 6.3 supplied by Tripos Associates of 1699 South
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