Syntheses and GABA uptake properties of 6-ether- and 6-enol ether-substituted nipecotic acids

Article abstract of DOI:10.1016/j.ejmech.2004.03.006

6-Aralkylether- and 6-arylenol-ether-substituted nipecotic acids were synthesized. These analogues are poor GABA uptake inhibitors. The electronegative region concept developed in the N-substituted nipecotic acid series cannot be transferred on the side c

Full text of DOI:10.1016/j.ejmech.2004.03.006

European Journal of Medicinal Chemistry 39 (2004) 633–638
www.elsevier.com/locate/ejmech
Preliminary Communication
Syntheses and GABA uptake properties of 6-ether- and 6-enol
ether-substituted nipecotic acids
Victor N’Goka a, Caterina Bissantz a, Philippe Bisel a, Tine B. Stenbøl b,
Povl Krogsgaard-Larsen b, Gilbert Schlewer a,*
a Laboratoire de pharmacochimie de la communication cellulaire UMR7081 du CNRS, faculté de pharmacie, 74, route du Rhin, 67401 Illkirch, France
b Department of Medicinal Chemistry, Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark
Received 11 December 2003; received in revised form 15 March 2004; accepted 22 March 2004
Available online 11 June 2004
Abstract
6-Aralkylether- and 6-arylenol-ether-substituted nipecotic acids were synthesized. These analogues are poor GABA uptake inhibitors. The
electronegative region concept developed in the N-substituted nipecotic acid series cannot be transferred on the side chain of this series of
6-substitued analogues.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Nipecotic acid; Ether; Enol ether; GABA; GABA uptake inhibitors
1. Introduction
It seemed interesting to us to transpose the electronegativ-
ity concept on 6-substituted derivatives to see if such modi-
fications could be transposed from the N-1 position to the
position 6 and to try to refine the localization of the electrone-
gative region.
We report the synthesis and the inhibitory properties of
6-substituted nipecotic acids bearing, ether-, enol ether-
aralkyl side chains.
A decrease of c-aminobutyric acid (GABA) 1, a major
inhibitory neurotransmitter [1–4], in pathologies such as
Parkinson disease [5], epilepsy [6,7], Huntington chorea [8],
schizophrenia [9] or Alzheimer disease [10] seems well es-
tablished. A possible pathway to restore the normal concen-
tration of this major neurotransmitter is to inhibit its uptake
mechanisms. Structure activity relationships around guva-
cine 2 and nipecotic acid 3 [4,11], two well known GABA
uptake inhibitors (Fig. 1), have been developed leading to
SKF 100300-A 4 and SKF 89976-A 5 which were active in
vitro at 0.6 and 0.33 µM, respectively, and in vivo at around
20 mg/kg [12–14]. A pharmacophore model has suggested
the synthesis of the 6-substituted guvacine derivative 6,
which was active in vitro at 0.1 µM [15]. The replacement of
the side chain double bound by an ether function where the p
electrons are replaced by the p electrons of the oxygen lone
pairs (compound 7) [4,16,17] or enol ether function (com-
pound 8) [18] led to equipotent and even more potent ana-
logues compared to the parent compounds 4 and 5. These
results were interpreted as a favorable effect of a so called
electronegative region.
2. Chemistry
The syntheses are described in Scheme 1. The hydroxym-
ethyl nicotinate (9) [19,20] reacted with diphenylmethanol in
the presence of an excess of pTSOH to give the ether 10. The
alcohol 9 reacted with aralkylhalide; formed the correspond-
ing ether 11 if a-mono arylhalides were used [21].
The alcohol 9 treated with CCl4/nBu3P [22] yields the
halide 12. The halide was substituted by the diphenylacetal-
dehyde enolate to form the side chain of the intermediate 13.
The pyridinic rings of 11 and 13 were then reduced by
means of NaBH3CN leading to diastereomeric mixtures of
the nipecotates 14–16 and 17–19. The diastereomers were
separated by classical column chromatography. Finally, the
esters 14–19 were hydrolyzed and the final products 20–25
kept as hydrochloride salts.
* Corresponding author. Tel.: +33-3-90-24-42-19;
fax: +33-3-90-24-43-10.
E-mail address: schlewer@pharma.u-strasbg.fr (G. Schlewer).
© 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.03.006

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V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 633–638
CO2H
CO2H
CO2H
H2N
N
H
N
H
GABA
1
2
3
CO2H
CO2H
CO2H
N
N
N
H
SKF 100300-A
SKF 89976-A
4
6
5
CO2H
CO2H
N
N
R
O
O
R
7
8
Fig. 1. Structures of GABA and known GABA uptake inhibitors.
3. Results and discussion
length is perhaps not optimum or its orientation inappropri-
ate to reach the electronegative region.
A hydrogen bond between the secondary NH group and
the ether oxygen atom could be evoked to induce a bad
conformation of the side chain, and to explain the observed
low affinities. But, previous work in the guvacine series
showed that N-methyl-6-ether substituted derivatives does
not lead to potent analogues (Table 3) [24].
More work is in progress. New analogues have to be
synthesized. Previous work in this field, the results that are
reported here, as well as the results of the future analogues
will be included in a conformational molecular modeling
study to refine the spatial localization of the electronegative
region and to explain the structure activity relationships.
The GABA uptake inhibitory properties of the final prod-
ucts were tested in vitro on rat brain synaptosome prepara-
tion [23]. The results are reported in Tables 1 and 2.
Compared to the corresponding N-substituted analogues
and also to the other reference compounds, the synthesized
products possess very low affinity as GABA uptake inhibi-
tors. Curiously, the esters showed sometimes more activity
than the corresponding acids even if this activity remained
low.
The trans- and cis-isomers possess the same low level of
affinity even if the trans-isomer fit better with the previously
published pharmacophore.
The introduction of the electronegative region concept on
6-substituted nipecotic analogues does not, so far, result in
active analogues, even if the length of the side chain was
determined according to the pharmacophore model, [15] this
4. Experimental part
Melting points (m.p.) were measured on a Mettler PF
62 apparatus and are uncorrected. If not specified, NMR

V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 633–638
635
CO2Et
CO2Et
N
10
N
a
O
OH
9
b
c
CO2Et
CO2Et
O
N
e
N
12
11
Cl
d
e
CO2Et
CO2Et
CO2Et
N
+
O
N
H
N
H
e
O
O
R
R
14-16
17-19
f
f
13
CO2H
CO2H
N
H
N
H
O
O
R
R
20-22
23-25
Scheme 1. (a) (C6H5)2CHOH, pTSOH; (b) Bu3P, CCl4; (c)NaH, pC6H5–C6H4–CH2OH; (d) NaH, (C6H5)2CHCHO; (e) NaBH3CN; (f) NaOH, then HCl.
Table 1
spectra were recorded on Bruker Avance 300 spectrometer
GABA uptake inhibitor properties for the synthesized ether analogues
using the d scale; the CHCl3 residual signal was fixed at
CO2R3
7.26 ppm. The abbreviations s, d, t, q, qu, m are related to
singlet, doublet, triplet, quadruplet, quintuplet and multiplet,
respectively. All the new compounds gave satisfactory CHN
analyses.
N
H
R2
O
4.1. Ethyl 2-(diphenyl-methyloxymethyl)-nicotinate (10)
R1
Benzhydrol (1.64 g, 8.27 mmol), alcohol 9 [19,20] and
p-toluenesulfonic acid (1.28 g, 6.70 mmol) were mixed in
toluene (90 ml) and refluxed overnight under azeotropic
distillation conditions. Toluene was evaporated and the resi-
due was partitioned between ethyl acetate and a saturated
NaHCO3 solution. The organic layer was dried over MgSO4,
filtered and concentrated in vacuo. The crude product was
flash chromatographied on a silica gel column; the expected
compound was eluted with hexane/ether (1:1) as a yellow oil
Number
R1
R2
R3
IC50 (µM)
0.60
4
5
6
7
SKF 100300-A
SKF 89976-A
0.33
0.10
CI966 (R = CF3)
0.44
8
0.10
14
15
20
21
C6H5
C6H5
H
C2H5
C2H5
H
>100
>100
>100
>100
p-C6H5–C6H4
C6H5
C6H5
H
p-C6H5–C6H4
H
1
(2.47 g, 86%). H-NMR (CDCl3): 1.42 (t, J = 7.3, 3H,

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V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 633–638
Table 2
4.3. Ethyl 2-(2,2-diphenyl-vinyloxymethyl)-nicotinate (13)
GABA uptake inhibitor properties for the synthesized enol ether analogues
CO2R3
NaH suspension (0.2 g, 5.0 mmol) was added to CH3CN
(5 ml) in a 25 ml flask kept under argon; the flask was cooled
in an ice bath. A solution of biphenylacetaldehyde (1.0 g,
5.0 mmol) in CH3CN (5 ml) was dropped, under stirring, into
the flask and stirring was continued for 45 min. Chlorometh-
ylpyridine 12 [22] (1.0 g, 5.0 mmol) dissolved in CH3CN
(2.5 ml) was then dropped into the mixture which was stirred
for 2 h. The mixture was filtered and the filtrate evaporated,
N
H
H
O
Noumber
R3
IC50 (µM)
1
giving the enol ether 13 as an oil (1.7 g, 92%). H-NMR
16
19
22
25
trans
cis
C2H5
C2H5
H
45
(CDCl3): 1.43 (t, J = 7.1, 3H, OCH2CH3), 4.43 (q, J = 7.2,
2H, OCH2CH3), 5.16 (s, 2H, CH2OCH=), 6.64 (s, 1H,
CH2OCH=), 7.3–7.6 (m, 11H, H-5 and (C6H5)2), 8.33 (dd,
J = 8.0, J = 2.0, 1H, H-4), 9.17 (d, J = 2.0, 1H, H-2).
46
trans
cis
>30 solubility
>100
H
OCH2CH3), 4.42 (q, J = 7.2, 2H, OCH2CH3), 4.74 (s, 2H,
CH2OCH), 5.55 (s, 1H CH(C6H5)2), 7.25–7.45 (m, 10H,
CH(C6H5)2), 7.71 (dd, J = 8.0, J = 0.7, 1H, H-3), 8.33 (dd,
J = 8.4, J = 2.2, 1H, H-4), 9.13 (dd, J = 2.2, J = 0.7, 1H, H-6).
4.4. Ethyl trans-6-(diphenyl-methyloxymethyl)-nipecotate
(14)
Pyridine 10 (1.03 g, 2.94 mmol) was dissolved in glacial
acetic acid (10 ml) at room temperature and placed under an
argon atmosphere. NaBH3CN (0.74 g, 11.9 mmol) was
slowly added and the mixture was stirred for 2 h at room
temperature and then heated at 50 °C for 1 h, kept at room
temperature overnight and finally ice cooled. Water (50 ml)
and concentrated sodium hydroxide were added until the
mixture was strongly basic. The mixture was extracted with
ethyl acetate, the organic layer was washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. The crude
product was flash chromatographied on a silica gel column;
the expected compound was eluted with ethyl acetate giving
the amine 14 as a yellow oil 700 mg/g, 34%). 1H-
NMR/COSY (CDCl3): 1.26 (t, J = 7.2, 3H, OCH2CH3),
1.0–1.35 (m, 1H, H-5ax), 1.45–1.6 and 1.6–1.7 (2m, 2H,
H-4ax and H-5eq), 2.05–2.15 (m, 1H, H-4eq), 2.46 (tt,
J = 11.7, J = 3.8, 1H, H-3ax), 2.73 (t, J = 11.5, 1H, H-2ax),
2.75–2.9 (m, 1H, H-6ax), 3.3–3.7 (m, 2H, H-2eq and H-8),
3.46 (B part of an ABX system, JAB = 9.0, JBX = 3.8, 1H,
H-8), 4.14 (q, J = 7.2, 2H, OCH2CH3), 5.36 (s, 1H,
OCH(C6H5)2), 7.2–7.4 (m, 10H, OCH(C6H5)2). The cis-
isomer was not obtained pure. The corresponding hydrochlo-
ric salt was obtained by dissolving the amine 14 (83.7 mg,
0.24 mmol) in methanol and adding 1 N HCl (0.6 ml). The
solution was evaporated to dryness. Water was added to the
residue, the aqueous solution was extracted with ether, frozen
and lyophilized giving the hydrochloride (78 mg, 85%) as a
white powder (m.p.: dec.); CHN; SM(EI) m/z: 355, 354, 274,
4.2. Ethyl trans-6-(p-phenyl-benzyloxymethyl)-nicotinate
(11)
A solution of the alcohol 9 [19,20] (3.33 g, 18.4 mmol) in
DMF (45 ml) was stirred, cooled in an ice bath and kept
under an argon atmosphere. NaH dispersion (0.81 g,
20.23 mmol) was added and stirring was maintained for 1 h.
A solution of p-phenylbenzylbromide (35.0 g, 20.23 mmol)
in DMF (35 ml) was slowly added and the mixture was
stirred overnight at room temperature. The crude product was
extracted by partition between water and ethyl acetate. The
organic layer was washed with brine and dried with MgSO4.
Purification by flash chromatography on a silica gel column
eluted with an ethyl acetate/hexane (3:7) mixture gave the
ether 11 as a yellow oil (2.18 g 34.2%). 1H-NMR (CDCl3):
1.43 (t, J = 7.2, 3H, OCH2CH3), 4.44 (q, J = 7.2, 2H,
OCH2CH3), 4.74 and 4.80 (2s, 4H, CH2OCH2), 7.3–7.5 (m,
9H, C6H5–C6H4), 7.62 (d, J = 8.1, 1H, H-3), 8.34 (dd, J = 8.1,
J = 2.1, 1H, H-4), 9.18 (d, J = 1.9, 1H, H-6).
Table 3
GABA uptake inhibitor properties for 6-ether substituted guvacines [24]
CO2R3
N
R4
R2
O
1
171, 167, 156(100), 152, 128, 110, 82, 56, 55; H-NMR
R1
(CD3OD): 1.28 (t, J = 7.2, 3H, OCH2CH3), 1.55–1.75 (m,
2H, H-5ax and H-5eq), 1.85–2.1 (m, 1H, H-4ax), 2.2–2.3 (m,
1H, H-4eq), 2.75 (tt, J = 12.1, J = 3.6, 1H, H-3ax), 3.08 (t,
J = 12.4, 1H, H-2ax), 3.3–3.4 (m, 1H, H-6ax), 3.45–3.6 (m,
2H, H-2eq and H-8), 3.69 (B part of an ABX system,
JAB = 10.6, JBX = 3.8, 1H, H-8), 4.19 (q, J = 7.2, 2H,
OCH2CH3), 5.51 (s, 1H, OCH(C6H5)2), 7.2–7.4 (m, 10H,
OCH(C6H5)2).
R1
R2
R3
C2H5
p-Cl–C6H4 C2H5
R4
IC50 (µM)
>100
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
H
p-Cl–C6H4
p-C6H5–C6H4
C6H5
>100
H
C2H5
H
>100
C6H5
>100
p-Cl–C6H4
p-C6H5–C6H4
p-Cl–C6H4
H
H
>100
H
>100

V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 633–638
637
4.5. Ethyl trans-6-(p-phenyl-benzyloxymethyl)-nipecotate
(15)
J = 3.7, 1H, H-2ax), and H-6ax), 3.49 (dt, J = 12.8, J = 2.2,
1H, H-2eq), 3.93 (AB part of an ABX system Dd = 0.09,
JAB = 10.2, JAX = 5.8, JBX = 4.0, 2H, CH2-8), 4.12 (q, J = 7.2,
2H, OCH2CH3), 6.52 (s, 1H, =CHO), 7.1–7.4 (m, 10H,
(C6H5)2).
Pyridine 11 (1.46 g, 4.20 mmol) was treated by the same
procedure as for the ester 14, giving the piperidine 15
(470 mg, 31.4%) as a yellow oil. 1H-NMR/COSY (CDCl3):
1.27 (t, J = 7.2, 3H, OCH2CH3), 1.0–1.35 (m, 1H, H-5ax),
1.45–1.6 and 1.6–1.75 (2m, 2H, H-4ax and H-5eq), 2.05–2.2
(m, 1H, H-4eq), 2.44 (tt, J = 11.7, J = 3.8, 1H, H-3ax), 2.71 (t,
J = 11.5, 1H, H-2ax), 2.75–2.85 (m, 1H, H-6ax), 3.3–3.45
(m, 2H, H-2eq and H-8), 3.52 (B part of an ABX system,
JAB = 9.2, JBX = 3.6, 1H, H-8), 4.14 (q, J = 7.2, 2H,
OCH2CH3), 4.58 (s, 1H, OCH(C6H5)2), 7.2–7.7 (m, 9H,
C6H4C6H5). The cis-isomer was not obtained pure enough.
The hydrochloride was obtained under the same conditions
4.7. Trans-6-(diphenyl-methyloxymethyl)-nipecotic acid
(20) (hydrochloride)
A mixture of the ester 14 (220 mg, 0.62 mmol) NaOH
(28 mg, 0.68 mmol), water (12.5 ml), and THF (6 ml) was
stirred overnight at room temperature. The mixture was
evaporated to dryness and the residue was washed with ether.
Water (1.0 ml) and HCl 37% (0.2 ml, 1.6 mmol) were added
to the residue. The solution was again evaporated and isopro-
panol was added to the residue. This solution was filtered and
dropped in anhydrous ether (100 ml). The precipitate was
filtered and dried yielding the acid 20 as a white powder
(m.p.: dec.) (75 mg, 35%); CHN; 1H-NMR/COSY
(CD3OD): 1.55–1.75 (m, 2H, H-5ax and H-5eq), 1.9–2.0 (m,
1H, H-4ax), 2.15–2.3 (m, 1H, H-4eq), 2.5–2.6 (m, 1H,
H-3ax), 3.05 (t, J = 12.3, 1H, H-2ax), 3.3–3.4 (m, 1H,
H-6ax), 3.45–3.6 (m, 2H, H-2eq and H-8), 3.70 (B part of an
ABX system, JAB = 10.4, JBX = 3.3, 1H, H-8), 5.51 (s, 1H,
OCH(C6H5)2), 7.2–7.4 (m, 10H, OCH(C6H5)2).
1
as for the amine 14; CHN; H-NMR (CD3OD): 1.27 (t,
J = 7.2, 3H, OCH2CH3), 1.45–1.7 (m, 2H, H-5ax and H-5eq),
1.85–2.0 (m, 1H, H-4ax), 2.15–2.3 (m, 1H, H-4eq), 2.68 (tt,
J = 11.9, J = 3.4, 1H, H-3ax), 2.97 (t, J = 12.2, 1H, H-2ax),
3.1–3.25 (m, 1H, H-6ax), 3.4–3.6 (m, 2H, H-2eq and H-8),
3.66 (B part of an ABX system, JAB = 10.2, JBX = 3.4, 1H,
H-8), 4.18 (q, J = 7.2, 2H, OCH2CH3), 4.64 (s, 2H,
OCH2(C6H4C6H5), 7.3–7.7 (m, 9H, C6H4C6H5).
4.6. Ethyl 6-(2,2-diphenyl-vinyloxymethyl)-nipecotates (16)
and (19)
4.8. Trans-6-(p-phenyl-benzyloxymethyl)-nipecotic acid
(21) (hydrochloride)
Pyridine 13 (3.0 g, 8.3 mmol) was dissolved in glacial
acetic acid (40 ml) and placed under an argon atmosphere.
NaBH3CN (2.0 g, 8.25 mmol) was slowly added under stir-
ring at room temperature. After 3 h stirring the reaction
mixture was diluted with ice cooled water (80 ml), made
alcaline by use of NaOH 2 M and extracted with ethyl acetate
(3 × 100 ml). The organic layer was dried over MgSO4,
filtered and concentrated in vacuo. The crude product con-
tains the two diasteromers which were separated by column
chromatography on silica gel eluted with ethyl acetate giving
1.4 g (46%) of the less polar product (trans-isomer 16) as an
oil and 0.70 g (23%) of the more polar product (cis-isomer
19) as an oil.
Ester 15 (285 mg, 0.81 mmol) was converted under iden-
tical conditions as for the acid 20 to yield the acid 21 as a
white powder (m.p.: dec.) (116 mg, 40%); CHN; H-NMR
(CD3OD): 1.6–1.8 (m, 2H, H-5ax and H-5eq), 1.9–2.05 (m,
1H, H-4ax), 2.2–2.35 (m, 1H, H-4eq), 2.71 (tt, J = 12.1,
J = 3.9, 1H, H-3ax), 3.07 (t, J = 12.6, 1H, H-2ax), 3.3–3.4 (m,
1H, H-6ax), 3.45–3.6 (m, 2H, H-2eq and H-8), 3.72 (B part
of anABX system, JAB = 10.4, JBX = 3.6, 1H, H-8), 4.67 (AB
Dd = 0.06, JAB = 12.3, 2H, OCH2C6H4C6H5), 7.3–7.7 (m,
9H, C6H4C6H5).
1
4.9. Trans-6-(2,2-diphenyl-vinyloxymethyl)-nipecotic acid
(22) (hydrochloride)
4.6.1. Trans-isomer 16
1H-NMR (CDCl3) 1.1–1.4 (m, 4H, containing at 1.26 (t,
J = 7.2, 3H, OCH2CH3) and H-5ax), 1.55 (qd, J = 12.4,
J = 4.1, 1H, H-4ax), 1.70 (dq, J = 12.8, J = 2.6, 1H, H-5eq),
1.9–2.2 (m, 1H, H-4eq), 2.44 (tt, J = 11.3, J = 3.8, 1H,
H-3ax), 2.70 (t, J = 11.3, 1H, H-2ax), 2.8–3.0 (m, 1H,
H-6ax), 3.31 (ddd, J = 9.2, J = 3.8, J = 1.5, 1H, H-2eq), 3.85
(AB part of anABX system Dd = 0.12, JAB = 10.2, JAX = 7.9,
JBX = 3.9, 2H, CH2-8), 4.14 (q, J = 7.2, 2H, OCH2CH3), 6.52
(s, 1H, =CHO), 7.2–7.5 (m, 10H, (C6H5)2).
The same procedure as for the acid 20 was used starting
from ester 16 (200 mg) yielding a white powder (100 mg,
49%), CHN, m.p. 168 °C, 1H-NMR (D2O): 1.4–1.8 (m, 2H,
H-5ax, H-4ax), 1.9–2.1 (m, 1H, H-4eq), 2.42 (tt, J = 11.7,
J = 4.1, 1H, H-3ax), 2.95 (t, J = 12.4, 1H, H-2ax), 3.3–3.5 (m,
2H, containing at 3.42 (ddd, J = 12.6, J = 3.7, J = 1.5, 1H,
H-2eq) and H-6ax), 4.06 (AB part of an ABX system,
Dd = 0.12, JAB = 11.3, JAX = 6.8, JBX = 3.8, 2H, =CHOCH2–
CH), 6.68 (s, 1H, =C=CHO–), 7.1–7.4 (m, 10H, (C6H5)2).
4.6.2. Cis-isomer 19
4.10. Cis-6-(2,2-diphenyl-vinyloxymethyl)-nipecotic acid
(25) (hydrochloride)
1H-NMR (CDCl3) 1.2–1.4 (m, 4H, containing at 1.26 (t,
J = 7.2, 3H, OCH2CH3) and H-5ax), 1.5–1.8 (m, 2H, H-4ax,
H-5eq), 2.1–2.3 (m, 1H, H-4eq), 2.62 (qu, J = 3.8, 1H,
H-3eq), 2.8–3.1 (m, 2H, containing at 2.91 (dd, J = 12.8,
The same procedure as for the acid 20 was used starting
from ester 19 (200 mg) yielding a white powder (110 mg,

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V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 633–638
54%), CHN, m.p. 226 °C, 1H-NMR (D2O): 1.6–1.8 (m, 1H,
H-5ax), 1.9–2.1 (m, 2H, H-4ax, H-5eq), 2.2–2.4 (m, 1H,
H-4eq), 2.98 (qu, J = 3.7, 1H, H-3eq), 3.20 (dd, J = 12.8,
J = 3.7, 1H, H-2ax), 3.5–3.6 (m, 1H, H-6ax), 3.65 (dt,
J = 12.8, J = 2.2, 1H, H-2eq), 4.09 (AB part of an ABX
[6] M. Ito, H. Mikawa, T. Tanigushi, Neurobiology 34 (1984) 235–238.
[7] D. Rating, H. Siemes, W. Löscher, J. Neurol. 230 (1983) 217–225.
[8] S.J. Enna, E.D. Bird, J.P. Bennett, D.B. Bylund, L.L. Iversen,
J.H. Snyder, New Engl. J. Med. 294 (1976) 1305–1307.
[9] J. Stevens, K. Wilson, W. Foote, Psychopharmacologia 39 (1974)
105–119.
system, Dd
=
0.04, JAB
=
15.0, JAX
=
9.4,
[10] P. Davies, Brain Res. 171 (1979) 319–327.
[11] G.A.R. Johnston, Nature 258 (1975) 627–628.
[12] L.M. Yunger, P.J. Fowler, P. Zarevics, P.E. Setler, J. Pharmacol. Exp.
Ther. 228 (1984) 109–115.
JBX = 4.1 2H, =CHOCH2–CH), 6.65 (s, 1H, =CHO), 7.1–7.4
(m, 10H, (C6H5)2).
[13] F.E. Ali, W.E. Bondinell, P.A. Dandridge, J.S. Frazee, E. Garvey,
G.R. Girard, C. Kaiser, T.W. Ku, J.J. Lafferty, G.I. Moonsammy,
H.J. Oh, J.A. Rushi, P.E. Setler, O.D. Stringer, J.W. Venslawsky,
B.W. Volpe, L.M. Yunger, J. Med. Chem. 28 (1985) 653–660.
[14] W. Löscher, Drug Future 11 (1986) 37–41.
Acknowledgements
We thank Inserm contract 892017 and CNRS for giving a
grant to V.N. and Mary H. Richards for proofreading the
manuscript.
[15] V. N’Goka, G. Schlewer, J.M. Linget, J.P. Chambon, C.G. Wermuth, J.
Med. Chem. 34 (1991) 2547–2557.
[16] E. Falch, P. Krogsgaard-Larsen, Eur. J. Med. Chem. 26 (1991) 69–78.
[17] S. Blorge, A. Black, H. Bockbrader, T. Chang, V.E. Gregor, S.J. Lob-
bestael, D. Nugiel, M.R. Pavia, L. Radulovic, T. Woolf, Drug Dev.
Res. 21 (1990) 189–193.
[18] K.E. Andersen, J.L. Sorensen, P.O. Huusfeldt, L.J.S. Knutsen, J. Lau,
B.F. Lundt, H. Petersen, P.D. Suzdak, M.D.B. Swedberg, J. Med.
Chem. 42 (1999) 4281–4291.
References
[1] S.J. Enna, The GABA Receptors, Humana Press, Clifton, New York,
1983.
[2] E. Roberts, T.N. Chase, D.B. Tower, GABA in Nervous System
Function, Raven Press, New York, 1976.
[19] I. Matsumoto, J. Yoshizawa, Chem. Abs. 79 (1973) 31912j.
[20] P. Bisel, J.P. Gies, G. Schlewer, C.G. Wermuth, Bioorg. Med. Chem.
Lett. 6 (1996) 3025–3028.
[21] C. Bissantz, P. Bisel, G. Schlewer, Synlett (1998) 133–134.
[22] J. Hooz, S.S.H. Gilani, Can. J. Chem. 46 (1968) 86–87.
[23] P.B. Ramsay, M.E. Krigman, P. Morel, Brain Res. 187 (1980) 383402.
[24] P. Bisel, Thesis Université Louis Pasteur, Strasbourg, 1993, pp. 117.
[3] P. Krogsgaard-Larsen, J. Scheel-Kruger, H. Kofold, GABA-
Neurotransmitters, Pharmacochemical, Biochemical and Pharmaco-
logical Aspects, Munksgaard, Copenhagen, 1979.
[4] P. Krogsgaard-Larsen, B. Frolund, K. Frydenvang, Curr. Pharm. Des.
6 (2000) 1193–1209.
[5] K.G. Lloyd, L. Shemen, O. Hornykiewicz, Brain Res. 127 (1977)
269–278.