Simple, potent, and selective pyrrole inhibitors of monoamine oxidase types A and B

Article abstract of DOI:10.1021/jm0256124

N-Benzyl- and N-propargyl-1H-pyrrole-2-carboxyamides and some related methylenamines were synthesized and tested for their monoamine oxidase types A and B inhibitory activity. 2-(N-Methyl-N-propargylaminomethyl)-1H-pyrrole (24) was the most potent MAO-A inhibitor of the series [K_i(MAO-A) = 0.0054 μM], but it was not selective. Inhibitors N-4-fluorobenzyl-1H-pyrrole-2-carboxamide (12) and N-cyclohexylmethyl-1H-pyrrole-2-carboxamide (25) showed the highest MAO-A selectivity indexes (SI) corresponding to 2025 and > 2500, respectively, while 2-(N-methyl-N-benzylaminomethyl)-1H-pyrrole (21) was the most selective MAO-B inhibitor, having an SI of 0.0057.

Full text of DOI:10.1021/jm0256124

J . Med. Chem. 2003, 46, 917-920
917
Ch a r t 1. Reversible (a) and Irreversible (b) MAO
Inhibitors
Sim p le, P oten t, a n d Selective P yr r ole
In h ibitor s of Mon oa m in e Oxid a se Typ es
A a n d B
Romano Silvestri,*,# Giuseppe La Regina,#
Gabriella De Martino,# Marino Artico,#
Olivia Befani,‡ Marianna Palumbo,‡
Enzo Agostinelli,*,‡ and Paola Turini‡
Dipartimento di Studi Farmaceutici, Universita` degli Studi
di Roma “La Sapienza”, P.le Aldo Moro, 5, I-00185 Roma,
Italy, and Dipartimento di Scienze Biochimiche “A.
Rossi-Fanelli” and Centro di Biologia Molecolare del CNR,
Universita` degli Studi di Roma “La Sapienza”, P.le Aldo
Moro, 5, I-00185 Roma, Italy
Received November 15, 2002
Abstr a ct: N-Benzyl- and N-propargyl-1H-pyrrole-2-carboxy-
amides and some related methylenamines were synthesized
and tested for their monoamine oxidase types A and B
inhibitory activity. 2-(N-Methyl-N-propargylaminomethyl)-1H-
pyrrole (24) was the most potent MAO-A inhibitor of the series
[Ki(MAO-A) ) 0.0054 µM], but it was not selective. Inhibitors
N-4-fluorobenzyl-1H-pyrrole-2-carboxamide (12) and N-cyclo-
hexylmethyl-1H-pyrrole-2-carboxamide (25) showed the high-
est MAO-A selectivity indexes (SI) corresponding to 2025 and
>2500, respectively, while 2-(N-methyl-N-benzylaminomethyl)-
1H-pyrrole (21) was the most selective MAO-B inhibitor,
having an SI of 0.0057.
and the atypical antidepressants.11 All antidepressant
drugs act by a modulation of the synaptic transmission
of monoamines 5-HT, A, NA, or D.12 Iproniazid (4) was
the prototype of MAO inhibitor introduced in therapy
since the 1957s.13 Iproniazid and tranylcipromine (5) are
irreversible and nonselective MAO inhibitors respon-
sible for some side interactions with other drugs and
certain foods. Because of their adverse actions, the
therapeutic applications of first-generation MAO inhibi-
tors have been diminished.14,15 Modern research on the
development of more reversible, selective, and safe
MAO-A inhibitors led to the launch of moclobemide16
(2, Roche, 1990), tetrindol17 (6, Center of Chemistry of
Moscow, 1992), and toloxatone16 (7, Sanofi-Synthe´labo,
1984). Today, a wide range of novel MAO-A inhibitors
are under clinical and preclinical trials.
Parkinson’s disease is a neurodegenerative syndrome
for which the main therapy is the amelioration of the
symptoms with L-DOPA and/or DA agonists.18 Selegiline
(3, L-deprenyl) is an irreversible but not highly selective
MAO-B inhibitor administered to gain the L-DOPA level
in Parkinson therapy as well as to reach a protective
effect in patients with the pre-Parkinson syndrome.19
In a recent survey, both 3 and L-DOPA at high doses
induce neuronal apoptosis.20 In contrast, low doses of 3
act as a neuroprotector by stopping the apoptotic
event.20
In tr od u ction . MAO (EC 1.4.3.4) is an outer mito-
chondrial membrane FAD containing enzyme1 found in
nearly all tissues. On the basis of their substrate and
inhibitor specificities, two major isoforms have been
described, the MAO-A and the MAO-B2,3 made up of
different polypeptides.4 The structure of human MAO-B
was recently resolved,5 and the molecular determinants
required for MAO selectivity were investigated.6,7 MAOs
are responsible for the major neurotransmitter degrad-
ing in the central nervous system (CNS) and peripheral
tissues.8 MAO-A preferentially catalyzes the oxidative
deamination of serotonin (5-HT), adrenaline (A), and
noradrenaline (NA) and is selectively inhibited by
clorgyline (1) and moclobemide (2) (Chart 1). MAO-B
mainly catalyzes the oxidative deamination of â-phene-
tylamine and benzylamine and is selectively inhibited
by selegiline (3). Both isoforms act either on dopamine
(DA) in vitro or on tyramine. In mankind, DA is
preferentially deaminated by MAO-B. Because of their
role in the metabolism of monoamine neurotransmitters,
MAO-A and MAO-B are thought to be involved in
psychiatric and neurological disorders such as depres-
sion and Parkinson’s disease, respectively.9
Depression is a widespread disabling disease with
social and economic consequences.10 Antidepressant
drugs currently marketed fall into four main selective
5-HT uptake inhibitors (SSRIs), the MAO-A inhibitors
Our decennial interest in heterocyclic bioisosters of
CNS agents21 motivated us to synthesize novel, simple,
and highly selective pyrrole-containing MAO inhibitors.
Investigation of structures 2 and 3 allowed the identi-
fication of some common structural features attributed
to the presence of (A) an aryl ring, (B) a nitrogen-
containing four-atom chain, (C) an electron-rich zone
due to the tertiary amino group in 2 or a triple bond in
* To whom correspondence should be addressed. For R.S.: fax, +39
06 491 491; e-mail, romano.silvestri@uniroma1.it; phone, +39 06 4991
3800. For E.A: fax, +39 06 444 0062; e-mail, enzo.agostinelli@
uniroma1.it; phone, +39 06 4991 0838.
#
Dipartimento di Studi Farmaceutici.
‡ Dipartimento di Scienze Biochimiche “A. Rossi-Fanelli” and Centro
di Biologia Molecolare del CNR.
10.1021/jm0256124 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003

918 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Letters
Ch a r t 2. Reference Models for the Novel MAO
Sch em e 1a
Inhibitors
3 (Chart 2). In fact, we planned the synthesis of
derivatives 8-26, bearing the structural requirements
A-C, after replacing the phenyl moiety with a pyrrole
nucleus. Because of the presence of a CdO function in
2 but not in 3, both amides and methylene derivatives
were synthesized and tested.
Ch em istr y. The synthesis of the title derivatives was
reached by heating 2-trichloroacetyl-1H-pyrrole22 with
the appropriate benzylamine N-methylbenzylamine,
N-methylpropargylamine, or 4-(2-aminoethyl)morpho-
line in the presence triethylamine to give N-benzyl-1H-
pyrrole-2-carboxamides (8, 12, 15, 18), N-benzyl,N-
methyl 1H-pyrrole-2-carboxamide (9), N-propargyl-N-
methyl 1H-pyrrole-2-carboxamide (23), or N-[2-(4-
a
(a) R1 ) H, R2 ) COCCl3, amine, (H5C2)3N, 60 °C, overnight;
(b) R1 ) H, CH3, R2 ) H, amine, HCOH, CH3COOH, 0 °C, 1 h; (c)
R3 ) H, CH3I, TBAS, C6H6-50% NaOH, room temp, overnight;
(d) R1 ) H, CH3I, TBAS, CH2Cl2-50% NaOH, room temp,
overnight.
Ta ble 1. Structures and Monoamine Oxidase Inhibitory
Activities of Derivatives 8-26a
morpholinyl)ethyl]-1H-pyrrole-2-carboxamide
(26),
respectively. The N-benzyl-1-methyl-1H-pyrrole-2-carbox-
amides 10, 13, 16, and 19 were obtained from N-benzyl-
1H-pyrrole-2-carboxamides 8, 12, 15, and 18 by a phase-
transfer reaction23 with iodomethane in benzene/50%
sodium hydroxide in the presence of tetrabutylammo-
nium hydrogensulfate (TBAS) as a catalyst. The N-ben-
zyl-N-methyl-1-methyl-1H-pyrrole-2-carboxamides 11,
14, 17, and 20 were obtained from N-benzyl-1H-pyrrole-
2-carboxamides 8, 12, 15, and 18 by a similar phase-
transfer reaction by using dichloromethane as a solvent.
In this way, amides 11, 14, 17, and 20 were alterna-
tively obtained starting from 10, 13, 16, 19. 2-(N-
Methyl-N-benzylaminomethyl)-1H-pyrrole (21), 2-(N-
methyl-N-benzylaminomethyl)-1-methyl-1H-pyrrole (22),
and 2-(N-methyl-N-propargylaminomethyl)-1H-pyrrole
(24) (Mannich bases) were obtained by treating pyrrole
or 1-methylpyrrole with N-methyl-N-benzylamine or
N-methyl-N-propargylamine, respectively, and formal-
dehyde in acetic acid at 0 °C (Scheme 1).
Biology. All compounds were tested on bovine brain
mitochondria, isolated according to Basford,24 and used
as a source of the two isoforms of MAO. The activities
of MAO-A and -B were determined by a fluorometric
method using kinuramine as substrate,25 in the pres-
ence of their specific inhibitors (L-deprenyl, 1 mM, to
estimate the MAO-A activity and clorgyline, 1 mM, to
assay the isoform B).
Ki(MAOA), Ki(MAOB),
compd R1
R2 R3 R4 R5
X
µM
µM
SIb
600
500
576
8
H
H
CH3
H
H
H
H
H
F
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
F
O
0.25
0.6
150
300
150
300
810
8
140
200
0.4
9
H
O
O
O
O
O
O
O
O
O
O
O
O
10
CH3
0.26
0.54
0.4
0.59
0.18
0.34
0.2
11
CH3 CH3
555
12
H
H
H
2025
13.5
750
588
2
0.42
555
12.5
1.2
0.0057
572
666
3.7
>2500
160
>87
1074
0.025
13
CH3
F
F
14
CH3 CH3
15
H
H
H
H
H
H
H
H
H
H
H
16
CH3
F
F
17
CH3 CH3
0.98
0.72
0.4
0.42
400
5
18
H
H
H
H
H
H
H
H
19
CH3
F
F
H
H
20
21
22
CH3 CH3
CH3
CH3 CH3
0.36
H2 3.5
H2 0.15
0.45
0.02
85
H
23
24
H
H
CH3
CH3
O
0.075
50
H2 0.0054
0.4
0.02
>1000
80
25
26
0.5
MCLc
CLGd
SLGe
11.5
0.054
38
>100
58
Resu lts a n d Discu ssion . The inhibitory activities
(Ki values) of test compounds 8-26 are reported in Table
1. All compounds act through a noncompetitive and
reversible mechanism. Enzymatic assays revealed po-
tent MAO-A or MAO-B inhibitory activity for some of
the compounds examined. With the exception of the
derivative 21, all test compounds showed MAO-A in-
hibitory activities at a submicromolar concentration,
0.97
a
Data represent mean values of at least three separate experi-
ments. SI: selectivity index ) Ki(MAO-B)/Ki(MAO-A). c MCL:
b
moclobemide.14 CLG: clorgyline.17 e SLG: selegiline.17
d
while five of these compounds (16, 17, 20, 21, and 24)
inhibited MAO-B in the submicromolar range. The
selectivity index (SI) values [SI ) Ki(MAO-B)/Ki(MAO-

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 919
A)] ranged from >2500 (25) to 0.0057 (21). The amides
showed SI values between 0.42 (17) and >2500 (25).
Compound 24 was the most potent MAO-A inhibitor
within the series [Ki(MAO-A) ) 0.0054 µM], but it was
not sufficiently selective [Ki(MAO-B) ) 0.02 µM, SI )
3.7]. Both amides 12 and 25 showed the most favorable
selectivity toward MAO-A with SI values of 2025 and
>2500, respectively. Such values were higher than those
of the reference drugs clorgyline (SI ) 1074) and
moclobemide (SI > 87). The two derivatives 21 and 24
showed the highest anti-MAO-B activities with just the
same Ki(MAO-B) ) 0.02 µM. In enzymatic assays,
compound 21 showed an interesting anti-MAO activity
[Ki(MAO-A) ) 3.5 µM, Ki(MAO-B) ) 0.02 µM, and SI )
0.0057], being more active than selegiline against the
MAO-A isoform. This compound displayed inhibitory
potency about 50 times higher than that of reference
drug selegiline against the MAO-B isoform. Thus, 21
was the most selective MAO-B inhibitor among the test
derivatives.
or para position (compare 11 with 17 and 20), while a
decrease of activity was observed when the fluorine was
introduced at the ortho position (compare 11 with 14).
In the fluorinated series, the N-methylation of pyrrole
did not affect the anti-MAO-A activity whereas the anti-
MAO-B activity increased 100, 500, and 80 times going
from the ortho to the meta and then to the para position
(compare 12 with 13, 15 with 16, and 18 with 19).
It is also worth noting that N-methylation of the NH-
CdO group did not increase the inhibitory potency
against the MAO-A isoform with the exception of the
derivative 14 (3 times higher than 16), whereas the anti-
MAO-B activity was diminished (compare 13 with 14)
or retained (compare 16 with 17 and compare 19 with
20).
When the benzyl group of 9 was replaced with a
propargyl group (compound 23), both anti-MAO-A (8
times) and anti-MAO-B (6 times) activities increased.
Reduction of the carbonyl group of 23 to a methylene
(compound 24) caused only a slight improvement of the
anti-MAO-A activity (about 14 times) but a dramatic
increase (2500 times) of the anti-MAO-B activity, whereas
the selectivity between MAO-A and MAO-B isoforms
was lowered.
Substitution of the benzyl group of 8 with a 2-(4-
morpholinyl)ethyl moiety gave 25, a pyrrole analogue
of moclobemide with higher potencies against MAO-A
(about 29 times) and MAO-B (about 10 times) and the
highest selectivity index (SI > 2500) within the test
compounds.
In conclusion, N-benzyl- and N-propargyl-1H-pyrrole-
2-carboxyamides and the related N-benzyl- and N-pro-
pargyl-1H-pyrrole-2-methylenamines were shown to be
simple, potent, and effective MAO inhibitors. The
biological results led us to discriminate between MAO-A
and MAO-B selectivity in terms of structural differ-
ences. The best anti-MAO-A activity was reached with
the N-propargylpyrrolylamine 24. Unfortunately, this
compound showed a low selectivity index also being very
active against the MAO-B isoform. The corresponding
amide 23, although 15-fold less active against the
MAO-A isoform, showed the best selectivity profile
because of its lower activity against MAO-B. The
maximum of selectivity was obtained when the prop-
argyl moiety of 23 was replaced by the less lipophilic
morpholinylethyl chain giving 25, the pyrrole analogue
of moclobemide. Some derivatives (16, 17, 20, and 24)
were found to be more active than the reference
compounds against MAO-B, but they lacked selectivity
against this isoform. The sole derivative with a selectiv-
ity index greater than selegiline (SI ) 0.025) was the
N-methyl-N-benzyl-2-pyrrolylmethylamine 21 (SI )
0.0057). These findings will be considered in planning
novel and selective MAO-A and MAO-B inhibitors.
Preliminary SARs were obtained from data of enzy-
matic experiments reported in Table 1.
We first examined derivatives without substituents
on the phenyl ring. Data of Table 1 clearly demonstrated
that in this series the N-methylation of the pyrrole did
not affect the MAO-A or the MAO-B inhibitory proper-
ties. This is exemplified by a comparison of unmeth-
ylated compounds 8 and 9 with their N-methylated
counterparts 10 and 11, respectively.
We also observed that the reduction of the carbonyl
group to a methylene had a dramatic effect on MAO-B
activity of unmethylated pyrroles with an increase of
15 000 times (compare 9 with 21), whereas it did not
influence the activity of the related N-methyl analogues
(compare 11 with 22). As far as the MAO-A isoform is
concerned, either the reduction of the CdO to a CH2
(compare 9 with 21 and 11 with 22) or the N-methyla-
tion of the pyrrole (compare 9 with 11 and compare 21
with 22) had poor influence on the inhibitory activities
of compounds 9, 11, 21, and 22.
When the phenyl ring of 8 was replaced by a cyclo-
hexyl, a slight reduction of anti-MAO-A activity (twice)
was balanced by an increase (about twice) of anti-
MAO-B activity (compare 8 with 26).
Further significant SAR indications were deduced by
examination of the fluoro-substituted phenyl deriva-
tives. In fact, the presence of a fluorine atom at the
ortho, meta, or para position of the phenyl ring was a
determinant for the inhibitory activities of both MAO
isoforms.
Independent of its position on the phenyl ring, a
fluorine atom did not remarkably influence the anti-
MAO activities of compounds 12-20. This is exemplified
by the fluoro derivative 14, which showed an inhibitory
potency only 3-fold higher than that of the parent
compound 11. In contrast, the position of the fluorine
atom on the phenyl ring was crucial for activity against
the MAO-B isoform. In fact, introduction of a fluorine
atom in the phenyl ring of 10 reinforced the anti-MAO-B
activity from 19 to 375 times (compare 10 with 13, 16,
and 19).
Our study is actually aimed at investigating more
deeply the molecular determinants for the MAO selec-
tivity through the synthesis of novel pyrrole derivatives
obtained by molecular modeling aided design.
Ack n ow led gm en t. The authors thank the Italian
MIUR (Ministero dell’Istruzione, dell’Universita` e della
Ricerca), the Ministero della Salute (1% Fondo Sanitario
Nazionale), and the MIUR-PRIN2001 for partial sup-
port.
The anti-MAO-B activities of the dimethyl derivatives
11, 14, 17, and 20 were strengthened about 600-700
times by the introduction of a fluorine atom at the meta

920 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Letters
(17) Medvedev, A. E.; Kirkel, A. A.; Kamyshanskaya, N. S.; Mosk-
vitina, T. A.; Axenova, L. N.; Gorkin, V. Z.; Andreeva, N. I.;
Golovina, S. M.; Mashkovsky, M. D. Monoamine oxidase inhibi-
tion by novel antidepressant tetrindole. Biochem. Pharmacol.
1994, 47, 303-308.
Su p p or tin g In for m a tion Ava ila ble: Preparative and
chemicophysical data for compounds 8-26. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Drukarch, B.; van Muiswinkel, F. L. Drug Treatment of Par-
kinson’s Disease. Biochem. Pharmacol. 2000, 59, 1023-1031.
(19) Cesura, A. M.; Pletscher, A. The new generation of monoamine
oxidase inhibitors. Prog. Drug Res. 1992, 33, 171-297.
(20) Walkinshaw, G.; Waters, C. M. Induction of apoptosis in cat-
echolaminergic PC12 cells by L-DOPA. Implications for the
treatment of Parkinson’s disease. J . Clin. Invest. 1995, 95, 2458-
2464.
Refer en ces
(1) Mondov`ı, B. Structure and function of amine oxidases; CRC
Press: Boca Raton, FL, 1985.
(2) Bach, A. W. J .; Lan, N. C.; J ohnson, D. L.; Abell, C. W.;
Bembenek, M. E.; Kwan, S. W.; Seeburg, P. H.; Shih, J . C. cDNA
cloning of human liver monoamine oxidase A and B: molecular
basis of differences in enzymatic properties. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 4934-4938.
(3) Abell, C. W.; Kwan, S.-W. Molecular characterization of monoam-
ine oxidases A and B. Prog. Nucleic Acid Res. Mol. Biol. 2001,
65, 129-156.
(4) Grimsby, J .; Lan, N. C.; Neve, R.; Chen, K.; Shih, J . C. Tissue
distribution of human monoamine oxidase A and B mRNA. J
Neurochem. 1990, 55, 1166-1169.
(21) (a) Stefancich, G.; Artico, M.; Corelli, F.; Silvestri, R.; De Feo,
G.; Mazzanti, G.; Durando, L.; Palmery, M. Ricerche su nuovi
agenti psicotropi. Sintesi ed attivita` farmacologica di derivati
della 5H-imidazo[2,1-c][1,4]benzodiazepina (Research on novel
psychotropic agents. Synthesis and pharmacological activity of
derivatives of 5H-imidazo[2,1-c][1,4]benzodiazepine). Farmaco,
Ed. Sci. 1985, 40, 429-441. (b) Artico, M.; Corelli, F.; Massa,
S.; Stefancich, G.; Avigliano, L.; Befani, O.; Marcozzi, G.;
Sabatini, S.; Mondov`ı, B. Inhibition of copper-dependent amine
oxidases by some hydrazides of pyrrol-1-ylbenzoic and pyrrol-
1-ylphenylacetic acids. J . Med. Chem. 1988, 31, 802-806. (c)
Stefancich, G.; Silvestri, R. Research on nitrogen containing
heterocyclic compounds. XVI. Synthesis of 1,3,4,14b-tetrahydro-
2,10-dimethyl-2H,10H-pyrazino-[2,1-d]pyrrolo[1,2-b][1,2,5]benzo-
triazepine (1:1) maleate (10-methyl-10-azaaptazepine). J . Het-
erocycl. Chem. 1989, 26, 745-746. (d) Stefancich, G.; Artico, M.;
Silvestri, R.; Pantaleoni, G. C.; Giorgi, R.; Palumbo, G. Research
on psycotropic agents. III. Antidepressant activity and neurop-
sycobehavioural effects of new 5H-pyrrolo[1,2-b][1,2,5]benzo-
triazepine derivatives. Farmaco 1990, 45, 7-27. (e) Morpurgo,
L.; Agostinelli, E.; Mondov`ı, B.; Avigliano, L.; Silvestri, R.;
Stefancich, G.; Artico, M. Bovine serum amine oxidase: half-
site reactivity with phenylhydrazine, semicarbazide, and aro-
matic hydrazides. Biochemistry 1992, 31, 2615-2621. (f) Artico,
M.; Silvestri, R.; Stefancich, G.; Avigliano, L.; Di Giulio, A.;
Maccarrone, M.; Agostinelli, E.; Mondov`ı, B.; Morpurgo, L.
Aromatic hydrazides as specific inhibitors of bovine serum amine
oxidase. Eur. J . Med. Chem. 1992, 27, 219-228. (g) Stefancich,
G.; Artico, M.; Silvestri, R. Research on psycotropic agents. IV.
Synthesis and neuropsychopharmacological effects of 1,3,4,14b-
tetrahydro-10-methyl-2H,10H-pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]-
benzotriazepine and its derivatives. Farmaco 1992, 47, 987-
999. (h) Corelli, F.; Artico, M.; Massa, S.; Stefancich, G.
Pyrrolodiazepines and related systems of pharmaceuticals inter-
est via intramolecular cyclizaztion reactions. Trends Heterocycl.
Chem. 1991, 2, 105-125.
(5) Binda, C.; Newoton-Vinson, P.; Huba´lek, F.; Edmondson, D. E.;
Mattevi, A. Structure of human monoamine oxidase B, a drug
target for the treatment of neurological disorders. Nat. Struct.
Biol. 2002, 9, 1-5.
(6) Moro´n, J . A.; Campillo, M.; Perez, V.; Unzeta, M.; Pardo, L.
Molecular determinants of MAO selectivity in
a series of
indolylmethylamine derivatives: biological activities, 3D-QSAR/
CiMFA analysis, and computational simulation of ligand rec-
ognition. J . Med. Chem. 2000, 43, 1684-1691.
(7) Gnerre, C.; Catto, M.; Leonetti, F.; Weber, P.; Carrupt, P.-A.;
Altomare, C.; Carotti, A.; Testa, B. Inhibition of monoamine
oxidases by functionalized coumarin derivatives: biological
activities, QSARs, and 3D-QSARs. J . Med. Chem. 2000, 43,
4743-4758.
(8) Shih, J . C.; Chen, K.; Ridd, M. J . Monoamine oxidase: from
genes to behaviour. Annu. Rev. Neurosci. 1999, 22, 197-217.
(9) Checkoway, H.; Franklin, G. M.; Costa-Mallen, P.; Smith-Weller,
T.; Dilley, J .; Swansons, P. D.; Costa L. G. A genetic polymor-
phism of MAO-B modifies the association of cigarette smoking
and Parkinson’s disease. Neurology 1998, 50, 1458-1461.
(10) Andrews, J . M.; Nemeroff, C. B. Contemporary management of
depression. Am. J . Med. Chem. 1994, 97, 24S-32S.
(11) Hardman, J . G.; Limprid, L. E.; Goodmal Gilman, A. Drugs and
the treatment of psychiatric disorders. In Goodman and Gil-
man’s the pharmacological basis of therapeutics, 10th ed.;
Hardman, J . G., Limbird, L. E., Goodman Gilman, A., Eds.;
McGraw-Hill: New York, 2001; Chapter 19, pp 450-483.
(12) Shelton, R. C. Antidepressant therapy: new targets for drug
development. Expert Opin. Ther. Pat. 2001, 11, 1693-1711.
(13) Ban, T. A. Pharmacotherapy of depression: a historical analysis.
J . Neural Transm. 2001, 108, 707-716.
(22) Bailey, D. M.; J ohnson, R. E.; Albertson, N. F. Ethyl pyrrole-2-
carboxylate. Org. Synth. 1971, 51, 100-102.
(23) Keller, W. E. Phase Transfer Reactions; Georg Thieme Verlag:
Go¨ppingen, Germany, 1986.
(24) Basford, R. E. Preparation and properties of brain mitochondria.
Methods Enzymol. 1967, 10, 96-101.
(25) Matsumoto, T.; Suzuki, O.; Furuta, T.; Asai, M.; Kurokawa, Y.;
Rimura, Y.; Katsumata, Y.; Takahashi, I. A sensitive fluoromet-
ric assay for serum monoamine oxidase with kynuramine as
substrate. Clin. Biochem. 1985, 18, 126-129.
(14) Blackwell, B. Adverse effects of antidepressant drugs. 1. Monoam-
ine oxidase inhibitors and tricyclics. Drugs 1981, 21, 201-219.
(15) Bieck, P. R.; Antonin, K.-H. Tyramine potentiation during
treatment with MAOIs. In Clinical Advances in Monoamine
Oxidase Inhibitor Therapies; Kennedy, S. H., Ed.; American
Psychiatric Press: Washington, DC, 1994; pp 83-110.
(16) Curet, O.; Damoiseau, G.; Aubin, N.; Sontag, N.; Rovei, V.;
J arreau, F.-X. Befloxatone,
monoamino oxidase A inhibitor. J . Pharmacol. Exp. Ther. 1996,
277, 253-264.
a new reversible and selective
J M0256124