Synthesis and preliminary behavioural evaluation in mice of new 3-aryl-3-pyrrol-1-ylpropanamides, analogues of FGIN-1-27 and FGIN-1-43

Article abstract of DOI:10.1211/0022357011777945

The 2-aryl-3-indoleacetamides FGIN-1-27 and FGIN-1-43 have already been characterized in-vitro as potent and specific ligands for the mitochondrial DBI receptor. This affinity was associated with psychotropic properties in several rodent behavioural tasks (in particular anxiolytic action) via enhancement of GABA transmission through neurosteroid production. The synthesis of new 3-aryl-3-pyrrol-1-ylpropanamides 1a-i, analogues of FGIN-1-27 and FGIN-1-43, is described in four steps starting from the corresponding arylaldehydes. Preliminary evaluation of these compounds in behavioural studies (spontaneous locomotor activity and anxiolytic activity) in mice was also undertaken.

Full text of DOI:10.1211/0022357011777945

Journal of
Pharmacy and Pharmacology
JPP 2001, 53: 1561–1568
# 2001 The Authors
Received May 11, 2001
Accepted July 18, 2001
ISSN 0022-3573
Synthesis and preliminary behavioural evaluation in
mice of new 3-aryl-3-pyrrol-1-ylpropanamides,
analogues of FGIN-1-27 and FGIN-1-43
J. Guillon, M. Boulouard, V. Lelong, P. Dallemagne, S. Rault and C. Jarry
Abstract
The 2-aryl-3-indoleacetamides FGIN-1-27 and FGIN-1-43 have already been characterized in-
vitro as potent and specific ligands for the mitochondrial DBI receptor. This affinity was
associated with psychotropic properties in several rodent behavioural tasks (in particular
anxiolytic action) via enhancement of GABA transmission through neurosteroid production.
The synthesis of new 3-aryl-3-pyrrol-1-ylpropanamides 1a–i, analogues of FGIN-1-27 and FGIN-
1-43, is described in four steps starting from the corresponding arylaldehydes. Preliminary
evaluation of these compounds in behavioural studies (spontaneous locomotor activity and
anxiolytic activity) in mice was also undertaken.
Introduction
EA 2962–Pharmacochimie, UFR
des Sciences Pharmaceutiques,
Universite Victor Segalen
Bordeaux 2, 146 Rue Leo
Saignat, 33076 Bordeaux cedex,
France
The mitochondrial DBI receptor complex (mDRC; previously described as the
peripheral benzodiazepine receptors) is linked to the production of neurosteroids
such as pregnenolone sulfate, dehydroepiandrosterone sulfate and others. 2-Aryl-
3-indoleacetamides (FGIN-1-27 and FGIN-1-43) (Auta et al 1993; Kozikowski et
al 1993; Romeo et al 1993a, b) are potent and specific ligands for the mitochondrial
DBI receptor. In fact, these compounds bind specifically and with high affinity to
the peptide DBI receptor on mitochondrial membranes. They induce the production
of neurosteroids, which modulate GABA receptors, thus influencing behaviour
such as anxiety.
J. Guillon, C. Jarry
Centre d’Etudes et de Recherche
sur le Medicament de
Normandie, Laboratoire de
Pharmacochimie, UFR des
Sciences Pharmaceutiques, 1 Rue
Vaubenard, 14032 Caen cedex,
France
As part of our program concerning the 3-amino-3-arylpropionic acid derivatives
of therapeutic interest (Alsaidi et al 1994; Guillon et al 1996a, b, 1998a, b), we now
report the synthesis and preliminary behavioural evaluation in mice of new 3-aryl-
3-pyrrol-1-ylpropanamides 1a–i, analogues of FGIN-1-27 and FGIN-1-43. All
compounds were first evaluated in a large range of doses for spontaneous motor
activity in order to detect global psychotropic activity. An anxiolytic test was
undertaken in a model of unconditioned behaviour for the two most active
compounds. Variations in the length and number of the alkyl groups on the amide
nitrogen were probed together with the effects of halogen substituents on the aryl
ring to determine structure–activity relationships in comparison with the reference
compounds (Figure 1).
M. Boulouard, V. Lelong,
P. Dallemagne, S. Rault
Correspondence: J. Guillon, EA
2962 – Pharmacochimie, UFR des
Sciences Pharmaceutiques,
Universitie Victor Segalen
Bordeaux 2, 146 Rue Leo
Saignat, 33076 Bordeaux cedex,
France.
Funding: We are grateful to the
University of Bordeaux 2 and the
University of Caen for financial
support.
1561

1562
J. Guillon et al
3-(4-Fluorophenyl)-3-(pyrrol-1-yl)propanoic acid (5b)
White crystals (72%); mp 89–91mC; IR (KBr) ν: 3350–
2600 (OH), 1705 cm 1 (CO); 1H NMR (CDCl3) δ: 3.22
−
(1H, dd, J l 16.30 and 6.95, H-2b), 3.34 (1H, dd, J l
16.30 and 8.35, H-2a), 5.71 (1H, dd, J l 8.35 and 6.95,
H-3), 6.29 (2H, dd, J l 2.05 and 2.05, H-β), 6.82 (2H,
dd, J l 2.05 and 2.05, H-α), 7.07 (2H, dd, J l 8.65 and
8.45, H-3h and H-5h), 7.21 (2H, dd, J l 8.45 and 5.70,
H-2h and H-6h), 11.91 (1H, s, OH); 13C NMR (CDCl3)
δ: 35.6 (CH2), 53.1 (CH), 103.8 (C-β), 110.6 (d, 2J l 21.4,
C-3h and C-5h), 114.3 (C-α), 122.8 (d, 3J l 8.0, C-2h and
4
1
C-6h), 131.0 (d, J l 2.15, C-1h), 157.2 (d, J l 245.4,
C-4h), 171.4 (CO). Anal. calcd. for C13H12FNO2 : C, 66.94;
H, 5.18; N, 6.00. Found: C, 66.88; H, 5.14; N, 6.09%.
Figure 1 Structures of FGIN-1-27 and FGIN-1-43 and general
structure of new compounds 1a–i.
3-(4-Chlorophenyl)-3-(pyrrol-1-yl)propanoic acid (5c)
Beige crystals (29%); mp 84–86mC; IR (KBr) ν: 3385–
Materials and Methods
2700 (OH), 1715 cm 1 (CO); 1H NMR (CDCl3) δ: 3.15
−
(1H, dd, J l 16.30 and 6.85, H-2b), 3.27 (1H, dd, J l
16.30 and 8.20, H-2a), 5.62 (1H, dd, J l 8.20 and 6.85,
H-3), 6.20 (2H, dd, J l 2.05 and 2.05, H-β), 6.73 (2H,
dd, J l 2.05 and 2.05, H-α), 7.09 (2H, d, J l 8.45, H-3h
and H-5h), 7.31 (2H, d, J l 8.45, H-2h and H-6h), 11.74
(1H, s, OH); 13C NMR (CDCl3) δ: 39.9 (CH2), 57.7
(CH), 108.4 (C-β), 118.9 (C-α), 126.9 (C-3h and C-5h),
128.4 (C-2h and C-6h), 133.4 (C-1h), 138.2 (C-4h), 175.6
(CO). Anal. calcd. for C13H12ClNO2 : C, 62.53; H, 4.84;
N, 5.61. Found: C, 62.47; H, 4.69; N, 5.43%.
Chemical procedures
Melting points were determined with an SM-LUX-POL
Leitz hot-stage microscope and are uncorrected. The IR
spectra were recorded on a Bruker IFS-25 spectro-
meter. 1H NMR spectra were recorded on a Bruker AC
200 spectrometer (200 MHz) using deuteriochloroform
as solvent. Chemical shifts (δ ppm) refer to tetra-
methylsilane, which was used as an internal reference.
OH appeared as singlets exchangeable with D2O. Key:
t l triplet, s l singlet, d l doublet, dd l double doub-
let, m l multiplet. Elemental analyses (C, H, N) were
performed by CNRS, Vernaison, France and agreed
with the proposed structures to withinp0.3% of the
theoretical values.
3-(4-Methylphenyl)-3-(pyrrol-1-yl)propanoic acid
(5d)
White crystals (69%); mp 97–98mC; IR (KBr) ν: 3320–
2700 (OH), 1710 cm 1 (CO); 1H NMR (CDCl3) δ: 2.41
−
(3H, CH3), 3.23 (1H, dd, J l 16.30 and 7.00, H-2b), 3.33
(1H, dd, J l 16.30 and 8.30, H-2a), 5.69 (1H, dd, J l
8.30 and 7.00, H-3), 6.27 (2H, dd, J l 2.10 and 2.10,
H-β), 6.82 (2H, dd, J l 2.10 and 2.10, H-α), 7.15 (2H, d,
J l 8.15, H-2h and H-6h), 7.22 (2H, d, J l 8.15, H-3h and
H-5h), 11.19 (1H, s, OH); 13C NMR (CDCl3) δ: 21.1
(CH3), 40.8 (CH2), 58.8 (CH), 108.7 (C-β), 119.6 (C-α),
126.3 (C-2h and C-6h), 129.6 (C-3h and C-5h), 137.3
(C-4h), 137.9 (C-1h), 176.7 (CO). Anal. calcd. for
C14H15NO2 : C, 73.34; H, 6.59; N, 6.11. Found: C, 73.50;
H, 6.69; N, 6.19%.
General procedure for the preparation of
3-aryl-3-(pyrrol-1-yl)propanoic acids (5a–e)
To a solution of 3-amino-3-arylpropionic acid (2a–e)
(0.125 ) in 150 mL acetic acid, 2,5-dimethoxytetra-
hydrofuran (0.125 ) was added. The reaction mixture
was refluxed for 1 h and then evaporated to dryness.
The residue was triturated with water and then extracted
twice with 150 mL diethyl ether. The organic layer was
washed with 200 mL water, dried over sodium sulfate
and evaporated under reduced pressure to give com-
pounds 5a–e, which were purified by chromatography
on silica gel using ethyl acetate–cyclohexane (20:80, 3-(4-Methoxyphenyl)-3-(pyrrol-1-yl)propanoic acid
(5e)
v\v) as eluent.
White crystals (71%); mp 102–104mC; IR (KBr)
ν: 3300–2550 (OH), 1715 cm 1 (CO); 1H NMR (CDCl3)
−
3-Phenyl-3-(pyrrol-1-yl)propanoic acid (5a)
White crystals (75%); mp 120–121mC (Carceller et al δ: 3.14 (1H, dd, J l 16.20 and 8.00, H-2b), 3.23 (1H, dd,
1993; Tembo et al 1993).
J l 16.20 and 7.05, H-2a), 3.77 (3H, s, CH3O), 5.59 (1H,

1563
New analogues of FGIN-1-27 and FGIN-1-43
dd, J l 8.00 and 7.05, H-3), 6.15 (2H, dd, J l 2.00 and t, J l 6.30, CH3), 1.25 (12H, m, CH2), 1.42 (4H, m,
2.00, H-β), 6.71 (2H, dd, J l 2.00 and 2.00, H-α), 6.85 CH2), 3.11 (4H, m, NCH2), 3.26 (2H, m, H-2), 5.84 (1H,
(2H, d, J l 8.25, H-3h and H-5h), 7.12 (2H, d, J l 8.25, dd, J l 8.00 and 6.95, H-3), 6.13 (2H, dd, J l 2.10 and
H-2h and H-6h), 11.19 (1H, s, OH); 13C NMR (CDCl3) 2.10, H-β), 6.69 (2H, dd, J l 2.10 and 2.10, H-α), 6.96
δ: 40.8 (CH2), 55.3 (CH3O), 58.4 (CH), 108.6 (C-β), (2H, dd, J l 8.70 and 8.55, H-3h and H-5h), 7.16 (2H,
114.2 (C-α), 119.4 (C-3h and C-5h), 127.5 (C-2h and C-6h), dd, J l 8.55and5.35, H-2handH-6h);13CNMR(CDCl3)
132.2 (C-1h), 159.3 (C-4h), 176.4 (CO). Anal. calcd. δ: 14.0 (CH3), 22.6 (CH2), 26.5 (CH2), 26.6 (CH2), 27.6
for C14H15NO3 : C, 68.55; H, 6.16; N, 5.71. Found: (CH2), 29.1 (CH2), 29.7 (CH2), 31.5 (CH2), 31.6 (CH2),
C, 68.47; H, 6.05; N, 5.56%.
39.6 (CH2), 46.4 (NCH2), 48.0 (NCH2), 59.1 (CH), 108.4
2
(C-β), 115.4 (d, J l 21.3, C-3h and C-5h), 119.7 (C-α),
3
4
128.3 (d, J l 8.10, C-2h and C-6h), 137.1 (d, J l 2.05,
1
C-1h), 162.2 (d, J l 245.05, C-4h), 168.6 (CO). Anal.
calcd. for C25H37FN2O: C, 74.96; H, 9.31; N, 6.99.
Found: C, 74.67; H, 9.36; N, 6.87%.
General procedure for the preparation of N,N-
dialkyl-3-aryl-3-(pyrrol-1-yl)propanamides (1a–i)
To a stirred solution of compounds 5a–e (21 m) in
80 mL acetone at 0mC, triethylamine (21 m) was added
dropwise. After 30 min, ethyl chloroformate (21 m)
was added dropwise at 0mC. After 30 min, dialkylamine
(21 m) was added under the same conditions. The
reaction mixture was refluxed for 3 h and then cooled at
room temperature. After filtration of the precipitate, the
filtrate was evaporated to dryness. The oily residue was
taken up in 150 mL methylene chloride. The organic
layer was washed with a 1  aqueous hydrochloric acid
solution (2i100 mL), then with a saturated aqueous
sodium hydrogenocarbonate solution (2i100 mL),
dried over sodium sulfate and evaporated to dryness.
The oily residue was purified by chromatography on
silica gel using chloroform as eluent.
N,N-Dihexyl-3-(4-chlorophenyl)-3-(pyrrol-1-
yl)propanamide (1c)
1
1
−
Orange oil (28%); IR (KBr) ν: 1645 cm (CO); H
NMR (CDCl3) δ: 0.86 (3H, t, J l 6.40, CH3), 0.88 (3H,
t, J l 6.40, CH3), 1.23 (12H, m, CH2), 1.43 (4H, m,
CH2), 3.10 (4H, m, NCH2), 3.25 (2H, m, H-2), 5.82 (1H,
dd, J l 8.20 and 7.00, H-3), 6.13 (2H, dd, J l 2.05 and
2.05, H-β), 6.67 (2H, dd, J l 2.05 and 2.05, H-α), 7.09
(2H, d, J l 8.20, H-3h and H-5h), 7.25 (2H, d, J l 8.20,
H-2h and H-6h); 13C NMR (CDCl3) δ: 13.4 (CH3), 21.9
(CH2), 25.9 (CH2), 26.0 (CH2), 26.9 (CH2), 28.5 (CH2),
30.8 (CH2), 30.9 (CH2), 38.7 (CH2), 45.7 (NCH2), 47.3
(NCH2), 58.4 (CH), 107.8 (C-β), 119.0 (C-α), 127.3
(C-3h and C-5h), 128.1 (C-2h and C-6h), 132.8 (C-1h), 139.2
(C-4h), 167.8 (CO). Anal. calcd. for C25H37ClN2O: C,
72.00; H, 8.94; N, 6.72. Found: C, 71.88; H, 9.12; N,
6.85%.
N,N-Dihexyl-3-phenyl-3-(pyrrol-1-yl)propanamide
(1a)
Pale yellow oil (38%); IR (KBr) ν: 1640 cm 1 (CO); 1H
−
NMR (CDCl3) δ: 0.85 (3H, t, J l 6.35, CH3), 0.88 (3H,
t, J l 6.35, CH3), 1.39 (12H, m, CH2), 1.45 (4H, m,
CH2), 3.11 (4H, m, NCH2), 3.24 (2H, m, H-2), 5.85 (1H,
dd, J l 8.10 and 7.00, H-3), 6.13 (2H, dd, J l 2.10 and
2.10, H-β), 6.70 (2H, dd, J l 2.10 and 2.10, H-α), 7.18
(2H, m, H-arom), 7.26 (3H, m, H-arom); 13C NMR
(CDCl3) δ: 13.6 (CH3), 13.7 (CH3), 22.1 (CH2), 26.1
(CH2), 26.2 (CH2), 27.2 (CH2), 28.7 (CH2), 31.1 (CH2),
31.2 (CH2), 39.1 (CH2), 46.0 (NCH2), 47.6 (NCH2), 59.3
(CH), 107.8 (C-β), 119.4 (C-α), 126.2 (C-3h and C-5h),
127.3 (C-1h), 128.2 (C-2h and C-6h), 140.8 (C-4h), 168.4
(CO). Anal. calcd. for C25H38N2O: C, 78.48; H, 10.01;
N, 7.32. Found: C, 78.19; H, 9.70; N, 7.21%.
N,N-Dihexyl-3-(4-methylphenyl)-3-(pyrrol-1-
yl)propanamide (1d)
Colourless oil (27%); IR (KBr) ν: 1645 cm 1 (CO); 1H
−
NMR (CDCl3) δ: 0.88 (3H, t, J l 6.30, CH3), 0.90 (3H,
t, J l 6.30, CH3), 1.27 (12H, m, CH2), 1.43 (4H, m,
CH2), 3.12 (4H, m, NCH2), 3.26 (2H, m, H-2), 5.83 (1H,
dd, J l 8.05 and 7.00, H-3), 6.13 (2H, dd, J l 2.00 and
2.00, H-β), 6.71 (2H, dd, J l 2.00 and 2.00, H-α), 7.09
(2H, d, J l 8.00, H-2h and H-6h), 7.12 (2H, d, J l 8.00,
H-3h and H-5h); 13C NMR (CDCl3) δ: 14.0 (CH3), 14.1
(CH3), 21.0 (CH2), 22.5 (CH2), 26.5 (CH2), 26.6 (CH2),
27.5 (CH2), 29.1 (CH2), 31.5 (CH2), 31.6 (CH2), 39.5
(CH2), 46.3 (NCH2), 47.9 (NCH2), 59.5 (CH), 108.1
(C-β), 119.7 (C-α), 126.5 (C-2h and C-6h), 129.3 (C-3h and
C-5h), 137.3 (C-4h), 138.2 (C-1h), 168.9 (CO). Anal.
N,N-Dihexyl-3-(4-fluorophenyl)-3-(pyrrol-1-
yl)propanamide (1b)
Pale yellow oil (52%); IR (KBr) ν: 1640 cm 1 (CO); 1H calcd. for C26H40N2O: C, 78.74; H, 10.16; N, 7.06.
−
NMR (CDCl3) δ: 0.86 (3H, t, J l 6.30, CH3), 0.88 (3H, Found: C, 78.90; H, 10.05; N, 6.91%.

1564
J. Guillon et al
N,N-Dihexyl-3-(4-methoxyphenyl)-3-(pyrrol-1-
yl)propanamide (1e)
162.1 (d, 1J l 245.9, C-4h), 168.6 (CO). Anal. calcd. for
C23H33FN2O: C, 74.15; H, 8.93; N, 7.52. Found: C,
Colourless oil (25%); IR (KBr) ν: 1645 cm 1 (CO); 1H 74.44; H, 9.10; N, 7.44%.
−
NMR (CDCl3) δ: 0.85 (3H, t, J l 6.60, CH3), 0.87 (3H,
t, J l 6.60, CH3), 1.24 (12H, m, CH2), 1.35 (4H, m,
N,N-Dibutyl-3-phenyl-3-(pyrrol-1-yl)propanamide
(1h)
CH2), 3.12 (4H, m, NCH2), 3.24 (2H, m, H-2), 5.79 (1H,
dd, J l 8.10 and 7.00, H-3), 6.10 (2H, dd, J l 2.00 and
2.00, H-β), 6.68 (2H, dd, J l 2.00 and 2.00, H-α), 6.82
(2H, d, J l 6.90, H-3h and H-5h), 7.12 (2H, d, J l 6.90,
H-2h and H-6h); 13C NMR (CDCl3) δ: 14.0 (CH3), 22.5
(CH2), 26.5 (CH2), 26.6 (CH2), 27.5 (CH2), 29.1 (CH2),
31.4 (CH2), 31.6 (CH2), 39.6 (CH2), 46.3 (NCH2), 47.9
(NCH2), 55.2 (CH3O), 59.2 (CH), 108.1 (C-β), 113.9
(C-3h and C-5h), 119.6 (C-α), 127.8 (C-2h and C-6h), 133.2
(C-1h), 159.0 (C-4h), 168.9 (CO). Anal. calcd. for
C26H40N2O2 : C, 75.68; H, 9.77; N, 6.79. Found: C,
75.49; H, 10.02; N, 6.85%.
White crystals (26%); mp 40–41mC; IR (KBr) ν:
1640 cm 1 (CO); 1H NMR (CDCl3) δ: 0.89 (3H, t, J l
−
7.00, CH3), 0.92 (3H, t, J l 7.00, CH3), 1.23 (4H, m,
CH2), 1.43 (4H, m, CH2), 3.10 (4H, m, NCH2), 3.28 (2H,
m, H-2), 5.88 (1H, dd, J l 7.90 and 6.95, H-3), 6.14 (2H,
dd, J l 2.10 and 2.10, H-β), 6.72 (2H, dd, J l 2.10 and
2.10, H-α), 7.19 (2H, m, H-arom), 7.29 (3H, m, H-
arom); 13C NMR (CDCl3) δ: 13.8 (CH3), 13.9 (CH3),
20.1 (CH2), 20.2 (CH2), 29.7 (CH2), 31.2 (CH2), 39.4
(CH2), 46.1 (NCH2), 47.7 (NCH2), 59.8 (CH), 108.2
(C-β), 119.8 (C-α), 125.6 (C-3h and C-5h), 127.7 (C-1h),
128.6 (C-2h and C-6h), 141.2 (C-4h), 168.9 (CO). Anal.
calcd. for C21H30N2O: C, 77.25; H, 9.26; N, 8.58.
Found: C, 77.50; H, 9.36; N, 8.57%.
N,N-Dipentyl-3-phenyl-3-(pyrrol-1-yl)propanamide
(1f)
White crystals (31%); mp 37–39mC; IR (KBr) ν:
1630 cm 1 (CO); 1H NMR (CDCl3) δ: 0.86 (3H, t, J l
−
N,N-Dibutyl-3-(4-fluorophenyl)-3-(pyrrol-1-yl)-
propanamide (1i)
6.55, CH3), 0.89 (3H, t, J l 6.55, CH3), 1.21 (8H, m,
CH2), 1.43 (4H, m, CH2), 3.08 (4H, m, NCH2), 3.25 (2H,
m, H-2), 5.86 (1H, dd, J l 8.10 and 7.05, H-3), 6.13 (2H,
dd, J l 2.05 and 2.05, H-β), 6.71 (2H, dd, J l 2.05 and
2.05, H-α), 7.18 (2H, m, H-arom), 7.27 (3H, m, H-
arom); 13C NMR (CDCl3) δ: 13.9 (CH3), 22.3 (CH2),
22.4 (CH2), 27.2 (CH2), 28.8 (CH2), 28.9 (CH2), 29.0
(CH2), 39.4 (CH2), 46.2 (NCH2), 47.9 (NCH2), 59.7
(CH), 108.1 (C-β), 119.7 (C-α), 126.5 (C-3h and C-5h),
127.6 (C-1h), 128.6 (C-2h and C-6h), 141.1 (C-4h), 168.8
(CO). Anal. calcd. for C23H34N2O: C, 77.92; H, 9.66; N,
7.90. Found: C, 78.10; H, 9.76; N, 8.05%.
White crystals (41%); mp 35–37mC; IR (KBr) ν:
1635 cm 1 (CO); 1H NMR (CDCl3) δ: 0.87 (3H, t, J l
−
7.05, CH3), 0.91 (3H, t, J l 7.05, CH3), 1.19 (4H, m,
CH2), 1.40 (4H, m, CH2), 3.08 (4H, m, NCH2), 3.27 (2H,
m, H-2), 5.84 (1H, dd, J l 7.95 and 7.00, H-3), 6.13 (2H,
dd, J l 2.10 and 2.10, H-β), 6.69 (2H, dd, J l 2.10 and
2.10, H-α), 6.96 (2H, dd, J l 8.85 and 8.65, H-3h and H-
5h), 7.17 (2H, dd, J l 8.65 and 5.30, H-2h and H-6h); 13C
NMR (CDCl3) δ: 13.7 (CH3), 13.8 (CH3), 20.0 (CH2),
20.1 (CH2), 29.7 (CH2), 31.2 (CH2), 39.5 (CH2), 46.1
(NCH2), 47.7 (NCH2), 59.1 (CH), 108.4 (C-β), 115.4 (d,
2J l 21.3, C-3h and C-5h), 119.6 (C-α), 128.3 (d, J l
3
7.80, C-2h and C-6h), 137.1 (d, 4J l 1.95, C-1h), 162.1 (d,
1J l 245.0, C-4h), 168.6 (CO). Anal. calcd. for
C21H29FN2O: C, 73.22; H, 8.48; N, 8.13. Found: C,
73.03; H, 8.64; N, 8.11%.
N,N-Dipentyl-3-(4-fluorophenyl)-3-(pyrrol-1-yl)-
propanamide (1g)
White crystals (25%); mp 44–45mC; IR (KBr) ν:
1630 cm 1 (CO); 1H NMR (CDCl3) δ: 0.85 (3H, t, J l
−
7.00, CH3), 0.89 (3H, t, J l 7.00, CH3), 1.24 (8H, m,
CH2), 1.39 (4H, m, CH2), 3.11 (4H, m, NCH2), 3.25 (2H,
m, H-2), 5.83 (1H, dd, J l 8.05 and 6.95, H-3), 6.13 (2H,
dd, J l 2.10 and 2.10, H-β), 6.68 (2H, dd, J l 2.10 and
2.10, H-α), 6.96 (2H, dd, J l 8.60 and 8.50, H-3h and H-
Pharmacological procedures
Animals
5h), 7.15 (2H, dd, J l 8.50 and 5.45, H-2h and H-6h); 13C Male OF-1 mice (Iffa Credo), 20–24 g, were used for the
NMR (CDCl3) δ: 13.9 (CH3), 22.3 (CH2), 22.4 (CH2), pharmacological studies. The animals were allowed free
27.2 (CH2), 28.8 (CH2), 29.0 (CH2), 29.1 (CH2), 39.5 access to food and water. They were housed at a
(CH2), 46.3 (NCH2), 47.9 (NCH2), 59.1 (CH), 108.4 (C- temperature of 21–22mC and maintained under a 12-h
β), 115.4 (d, 2J l 21.2, C-3h and C-5h), 119.6 (C-α), 128.2 light–dark cycle. Behavioural testing was conducted
(d, 3J l 8.50, C-2h and C-6h), 137.1 (d, 4J l 2.95, C-1h), during the dark phase of the cycle (1300–1800 h). All

1565
New analogues of FGIN-1-27 and FGIN-1-43
experiments were conducted in accordance with the results were analysed using analysis of variance followed
Principles of Laboratory Animal Care (NIH publication by the Fischer’s protected least significant difference
No. 85-23, revised 1985), European directives and (PLSD) test. P values ! 0.05 were considered sig-
French laws on animal experimentation.
nificant.
Results
Drugs
The test compounds 1a–1i and the pharmacological
references (chlorpromazine (Specia) for the photo-
actimetry test and diazepam (Roche) for light\dark
exploration test) were suspended in a 1% carboxy-
methylcellulose suspension and administered intra-
Chemistry
During the course of our work on the synthesis of new
heterocyclic compounds of potential therapeutic in-
terest, we recently described the access to numerous
3-amino-3-arylpropionic acids (2a–e) in 35–60% yields
starting from commercial arylaldehydes (Dallemagne et
al 1986; Rault et al 1987, 1991). The β-amino-acids 2a–e
were synthesized by the Rodionow-Johnson reaction
(Rodionow & Malewinskaja 1926; Johnson & Livak
1936; Profft & Becker 1965; Guillon et al 1998a, b;
Sonnet et al 2000) via the corresponding imines 3a–e
(Figure 2). Moreover, a not-negligible quantity (10–
25%) of dicarboxylic acids 4a–e was isolated as the
intermediate product of the well-known Knoevenagel
synthesis of cinnamic acids (Johnson 1942). Treatment
of 2a–e with 2,5-dimethoxytetrahydrofuran in boiling
acetic acid according to the Clauson-Kaas method
(Elming & Clauson-Kaas 1952; Clauson-Kaas & Tyle
1952), led to the arylpyrrolylpropanoic acids 5a–e
(Carceller et al 1993; Tembo et al 1993). The Clauson-
Kaas reaction represented an easy method for the prep-
aration of N-substituted pyrroles from primary amino
derivatives. The acids were converted to their mixed
anhydrides 6a–e with ethyl chloroformate in presence of
triethylamine, and these intermediates 6a–e reacted in-
situ with the dialkylamine of choice to afford the amides
1a–i, which were purified by chromatography on silica
gel using chloroform as eluent (Kozikowski et al 1993;
1
−
peritoneally in a volume of 10 mL kg . Controls
received the same amount of vehicle.
Locomotor activity
Locomotor activity (Boissier & Simon 1965) was
recorded for 15 min with a photocell activity meter
beginning 30 min after intraperitoneal administration
of each test drug (n l 12 for each dose).
Light/dark exploration test
For the light\dark exploration test (Costall et al 1989),
test boxes, constructed entirely of perspex, had two
compartments with 270-mm high walls. One compart-
ment (coloured matt black) measured 270i180 mm,
and the other (coloured matt white) measured 270i
270 mm (interior dimensions). Both compartments were
separated by a wall (470 mm high, to act as a light
separator) with a 70i70-mm opening in the base. The
boxes did not have a top cover. Each compartment was
independently illuminated: the white compartment with
a 100-W white bulb and the black compartment with a
40-W red bulb. Both bulbs were located 370 mm from
the floor of the box. Each mouse (n l 12 for each dose)
was placed in the center of the light\dark box, and then
measurements of the number of transitions between
light and dark compartments and of the time spent in
the light compartment were made over a 5-min period
starting 30 min after intraperitoneal administration of
the test compounds.
Statistical analysis
The result are expressed as meanps.e.m. of the scores
(number of interrupted beams in the photoactimetry
test and number of transitions and time in the light
compartment in the light\dark exploration test). The
Figure 2 Synthesis of the β-amino-acids 2a–e. Reagents: i.
CH3COONH4, CH2(COOH)2, C2H5OH.

1566
J. Guillon et al
Table 1 Effects of tested compounds 1a–i and chlorpromazine on
spontaneous activity in micea.
1
−
Compounds
Dose (mg kg
)
Number of interrupted beams
(meanps.e.m.)
Control
–
383p45
90p23***
51p28***
259p42
1a
100
4
Chlorpromazine
Control
–
1b
100
4
54p11**
66p17**
400p54
Chlorpromazine
Control
–
1c
100
4
133p31***
64p11***
367p65
Chlorpromazine
Control
–
Figure 3 Synthesis of amides 1a–i. Reagents: i. 2,5-dimethoxy-
tetrahydrofuran, AcOH; ii. (C2H5)3N, CH3COCH3, ClCOOC2H5 ; iii.
[CH3CH2(CH2)nCH2]2NH.
1d
100
4
34p9**
33p13**
320p37
Chlorpromazine
Control
–
1e
100
4
149p21**
34p6***
279p37
Chlorpromazine
Control
–
Renault et al 1999) (Figure 3). In the 13C NMR spectra
of the fluorine compounds 5b and 1b, g, f, the aromatic
carbon absorption exhibited four typical doublets at
110.6–115.4 ppm for C-3h and C-5h (2JCF l 21.2–
1f
100
4
244p48
24p7**
306p44
249p37
16p6***
435p33
87p29***
68p15***
282p74
Chlorpromazine
Control
–
1g
100
4
21.4 Hz), 122.8–128.2 ppm for C-2h and C-6h (3JCF
l
Chlorpromazine
Control
–
7.8–8.5 Hz), 131.0–137.1 ppm for C-1h (4JCF l 1.95–
2.95 Hz) and 157.2–162.2 ppm for C-4h (1JCF l 245.0–
245.9 Hz). The different measured aromatic coupling
constant values (JCF) were in accordance with those
described in the literature for para-fluorobenzene
derivatives (Stothers 1972; Pretsch et al 1989).
1h
100
4
Chlorpromazine
Control
–
1i
100
4
35p9*
28p8**
Chlorpromazine
a
1
−
All the compounds were tested at 0.1, 1, 10 and 100 mg kg , but only
results at 100 mg kg 1 are given. *P ! 0.05, **P ! 0.01, ***P ! 0.001
−
compared with control.
Pharmacology
Compounds 1a–i were first evaluated in a large range of
doses for spontaneous motor activity to detect global
psychotropic activity. Two pharmacological tests were central depressive activity. Compound 1b appeared to
1
used for the evaluation of the in-vivo central potential be the most active compound because at 10 mg kg it
−
activity – the photoactimetry test (Boissier & Simon produced a decrease of spontaneous activity similar to
1
−
1965) measuring spontaneous activity, and the black that induced by chlorpromazine at 4 mg kg (68p19
and white test box (Costall et al 1989), a model based on interrupted beams vs 66p17 for chlorpromazine).
fear of novelty. All compounds were evaluated in the
Anxiolytic properties of two of the most sedative
1
−
first model at four doses (0.1, 1, 10 and 100 mg kg ). compounds, 1b and 1c, were tested in a model of
These doses were selected in accordance with those unconditioned behaviour using the light\dark explo-
previously used for FGIN compounds in behavioural ration test. This model is known to be sensitive to
studies (Romeo et al 1993a, b). At the upper dose numerous antineophobic drugs (such as benzo-
1
−
(100 mg kg ), none of the compounds 1a–i revealed diazepines or 5-HT1A agonists) and also to many com-
strong acute toxic effects (i.e. no prostration no con- pounds that increase neurosteroid production. Under
vulsion and no tremor) and no mortality was observed the experimental conditions, at doses of 1, 2.5 and 5 mg
1
at 48 h. The pharmacological data for the 100 mg kg
kg 1 (no sedative effect), the compounds did not present
−
−
dose are given in Table 1. They distinguished between significant anxiolytic activity (Table 2). Under the same
compounds 1f and 1g with no sedative activity, com- conditions, diazepam, which was used as a reference
pounds 1a, 1h and 1i with mild sedative activity and compound, induced anxiolytic behaviour at doses of 2.5
compounds 1b, 1c, 1d and 1e, which presented high and 5 mg kg 1 (Table 2).
−

1567
New analogues of FGIN-1-27 and FGIN-1-43
Table 2 Pharmacological data of compounds 1b, 1c and diazepam in the light\dark exploration test.
1
−
Compounds
Dose (mg kg
)
Number of transitions
Time in light (white) compartment(s)
(meanps.e.m.)
(meanps.e.m.)
Control
1b
–
12p2.7
9.6p1.8
11.5p2.5
7.5p1.7
11.5p2.7
11.2p1.9
9.5p2.4
10.6p2.1
8.5p1.5
6.7p1.3
18p4.4*
12p2.5
57p13
46p17
52p16
39p15
46p13
49p17
41p14
52p15
36.3p7.5
39.5p8.2
89.9p12*
85.6p17*
1
1b
2.5
5
1b
Control
1c
–
1
1c
2.5
5
1c
Control
Diazepam
Diazepam
Diazepam
–
1
2.5
5
*P ! 0.05 compared with control.
Discussion
which are structurally similar to FGIN-1-27 and FGIN-
1-43, presented the highest sedative activity. These re-
sults suggest a psychotropic profile different from that
of the FGIN-1 references and further investigations are
required to specify the mechanism of central depressive
activity.
In this work, we synthesized new analogues of com-
pounds FGIN-1-27 and F-GIN-1-43 previously charac-
terized in-vitro as potent and specific ligands for the
mitochondrial DBI receptor. We chose to change the in-
dole ring for a pyrrole ring, whereas we preserved the
dialkylation on the amide nitrogen by long and alkyl
chains as the para substitution of the phenyl ring on the
indole nitrogen. The presence of those two last structural
items in FGIN-1 derivatives appears to be essential for
binding to the mitochondrial DBI receptor complex
(Romeo et al 1993a, b). In mice, the in-vivo preliminary
pharmacological studies of the new products 1a–i
showed a central depressive activity characterized by a
decrease of the spontaneous activity. As a general rule,
we noted that the most active compounds, 1b–e, bore
two n-hexyl groups on the amide nitrogen and substitu-
ents located at the para position of the 3-aryl ring.
Moreover, compounds 1b and 1c, which present some
structural similarities with FGIN-1-27 and FGIN-1-43
(with fluoro and chloro substituents on the phenyl ring,
respectively), exhibited the most intensive depressive
activity. However, they showed no significant anxiolytic
activity in the black and white test box. This is probably
related to a different psychotropic profile compared
with those of the FGIN-1 reference compounds.
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