Synthesis and biological evaluation of 3,7-diazabicyclo[4.3.0]nonan-8-ones as potential nootropic and analgesic drugs

Article abstract of DOI:10.1021/jm101376k

A series of cis and trans 3,7-diazabicyclo[4.3.0]nonan-8-ones has been synthesized and tested for their ability to revert scopolamine-induced amnesia in the mouse passive-avoidance test. The racemates of the most potent compounds 4 and 7 were separated and tested, but no enantioselectivity was found for the nootropic activity. Compounds 4 and 7 and their enantiomers displayed interesting antihyperalgesic activity in two models of neuropathic pain (streptozotocin-induced and oxalilplatin-induced neuropathy) in comparison with pregabalin.

Full text of DOI:10.1021/jm101376k

BRIEF ARTICLE
pubs.acs.org/jmc
Synthesis and Biological Evaluation of 3,7-Diazabicyclo[4.3.0]nonan-
8-ones as Potential Nootropic and Analgesic Drugs
Elisabetta Martini,† Lorenzo Di Cesare Mannelli,‡ Gianluca Bartolucci,† Carlo Bertucci,§ Silvia Dei,†
Carla Ghelardini,‡ Luca Guandalini,† Dina Manetti,† Serena Scapecchi,† Elisabetta Teodori,†
and Maria Novella Romanelli*,†
†Department of Pharmaceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
‡Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
§Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
S Supporting Information
b
ABSTRACT: A series of cis and trans 3,7-diazabicyclo[4.3.0]nonan-8-ones has been synthesized and tested for their ability to revert
scopolamine-induced amnesia in the mouse passive-avoidance test. The racemates of the most potent compounds 4 and 7 were
separated and tested, but no enantioselectivity was found for the nootropic activity. Compounds 4 and 7 and their enantiomers
displayed interesting antihyperalgesic activity in two models of neuropathic pain (streptozotocin-induced and oxalilplatin-induced
neuropathy) in comparison with pregabalin.
’ INTRODUCTION
not show affinity toward the most important central receptors or
transporters. These compounds are able to increase acetylcholine
release from rat brain and nitric oxide production in rat adipo-
cytes, the latter effect being antagonized by nicotinic antagonists
such as mecamylamine and methyllycaconitine.11 There is
evidence that AMPA receptors are involved in the cognition-
enhancing effect of these compounds.12 However, a direct
interaction of 1 and 2 with nicotinic or AMPA receptors in vitro
has not been proven yet.
In order to find new potent compounds, some 3,7-diazabicyclo-
[4.3.0]nonan-8-ones4-9were designed. These substances represent
rigid analogues of 4-acetylaminopiperidines, such as 3a where the
acetamido group has been constrained into a 2-oxopyrrolidine ring.
The substituents on the nitrogen atom in position 3 were chosen
among those giving, in the previous series, the most interesting results.
The ring closure introduces two stereogenic centers into the mole-
cule. Both the cis and trans isomers were studied, and in order to study
enantioselectivity, the enantiomers of the most active compounds
(4 and 7) were prepared. Compounds 4-9 were tested for their
cognition-enhancing activity in the mouse passive avoidance test;
moreover, since piracetam-like nootropics show interesting analgesic
properties, their antihyperalgesic activity in two models of neuropathic
pain was determined. Interestingly, two structural analogues of 1 were
already reported to possess antihyperalgesic activity on the chronic
constriction injury model of neuropathic pain.13
Cognition enhancers, or nootropics, are compounds that
stimulate cognitive performance, acting through several different
mechanisms, such as the modulation of signal transduction
cascade or neurogenesis.1 These substances can be useful in
several kinds of cognitive dysfunctions, such as age-related
memory deficits, neurodegenerative disorders, other neuropsy-
chiatric conditions such as schizophrenia, and attention-deficit
hyperactivity disorders.2-6 Among nootropics, piracetam and
piracetam-like compounds (Chart 1) have been studied for
almost 4 decades and a few members of the family are in use in
several countries as drugs to control cognition impairment, to
afford neuroprotection after stroke, and to treat epilepsy.7,8
Although these substances are in general well tolerated, their
use as nootropics is controversial because of the lack of a
common mechanism of action at the molecular level. As a matter
of fact, some members of the series have been shown to modulate
neurotransmitter receptors (i.e., aniracetam, nefiracetam) or to
bind to synaptic vesicle 2A protein (i.e., levetiracetam,
brivaracetam). For others, such as the lead compound piracetam,
the biological target has not been identified yet. Interestingly, for
some members of this class, like those reported in Chart 1, the
efficacy in some models of neuropathic pain has been shown,9
although the mechanism of action is still unknown.
It has previously been reported that 1 (DM232, Chart 1) and
2 (DM235, Chart 1) show potent cognition-enhancing proper-
ties. Compound 1 shares some structural similarity with pirace-
tam (the 2-oxopyrrolidine ring); however, 1 and its analogues 2
and 3a (MN19, Chart 1), where the 2-oxopyrrolidine ring is no
longer present, are 3-4 orders of magnitude more potent than
piracetam.10 These compounds are well tolerated in rodents, but
their potential development has been hindered because their
mechanism of action has not been clarified. In fact, 1 and 2 did
’ CHEMISTRY
Compounds 4-9 were prepared according to Scheme 1.
Commercially available N-benzylpiperidone was transformed
into ester 10 by treatment with LDA and ethyl bromoacetate.
Received: October 22, 2010
Published: March 07, 2011
r
2011 American Chemical Society
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|

Journal of Medicinal Chemistry
BRIEF ARTICLE
Chart 1
Scheme 2a
a (a) n-BuLi, (R)-BnOCH(CH3)COCl, THF, -78 °C; (b) chromato-
graphic separation; (c) LiOH, 30% H2O2,THF/H2O; (d) H2/Pd/C, abs
EtOH; (e) 4-F-C6H4-SO2Cl, Et3N, CH3CN.
Scheme 1a
25% yields after two separations. Compounds 16a and 16b were
treated separately with lithium hydroperoxide according to
Evans,14 to obtain (þ)-11 and (-)-11. Catalityc hydrogenation
followed by treatment with 4-fluorobenzenesulfonyl chloride
gave (þ)-4 and (-)-4. Their enantiomeric excess was the same
as the commercially available (R)-2-benzoyloxypropionic acid
(97%),15 as shown by the NMR spectrum of 16a and 16b.
The same sequence of reactions was attempted on 12. On this
isomer chromatographic separation was more efficient, but the
hydrolysis of diastereoisomers 17a and 17b proved to be difficult,
since only small amounts of (þ)-12 and (-)-12 were obtained, the
main product (18) deriving from hydrolysis of the endocyclic amide
linkage. Therefore, (þ)-7and (-)-7were obtained by chiral HPLC
separation of rac-7 on Chiracel OD-H using 2-propanol-hexane as
mobile phase, with ee higher than 99% (see Supporting In-
formation). The low availability of the enantiomers of 4 and 7 did
not allow the determination of their absolute configuration.
a (a) LDA, BrCH2COOEt, THF, -78 °C; (b) AcONH4, NaBH3CN,
MeOH; (c) chromatographic separation; (d) 100 °C; (e) H2/Pd/C, abs
EtOH; (f) RCl, Et3N, CH3CN.
Reductive amination with ammonium acetate gave a 2:1 mixture
of cis and trans 3-benzyl-3,7-diazabicyclo[4.3.0]nonan-8-ones 11
and 12, which were separated by column chromatography.
A small amount of trans ethyl 2-(4-amino-1-benzylpiperidin-
3-yl)acetate 13 was recovered and transformed into 12 by
heating at 100 °C. Catalytic hydrogenation, followed by treat-
ment of 14 and 15 with 4-fluorobenzenesulfonyl chloride,
benzoyl chloride, or isopropylsulfonyl chloride gave, respectively,
cis derivatives 4-6 and their trans analogues 7-9.
The cis and trans stereochemistry was assessed by means of
NMR. The NOESY spectrum of 4 showed a correlation between
the peaks relative to H-1 and H-6, which are absent in the NOESY
spectrum of 7, allowing the assignment of a cis configuration to 4 and
the trans configuration to 7. In addition, the NOESY spectrum of 7
showed interactions between H-6 and protons in positions 2 and 4,
which are closer in space in the trans isomer with respect to the cis one.
These correlations were absent in the NOESY spectrum of 4. Other
evidence is reported in the Supporting Information.
’ PHARMACOLOGY
The compounds were tested for their ability to revert scopo-
lamine-induced amnesia in the mouse passive-avoidance test of
Jarvik and Kopp,16 slightly modified by us (see Supporting In-
formation). The compounds were dissolved in saline and tested ip
up to a dose of 10 mg/kg. The results are expressed as the minimal
effective dose (MED, mg/kg) and are reported in Table 1, in
comparison with piracetam, 3a, and previously described 4-amino-
piperidines 3b and 3c.17 Compounds were considered inactive if
they did not show activity up to a dose of 10 mg/kg, which is
4 orders of magnitude higher than the MED of the leads 1 and 2.
The antihyperalgesic activity of 4 and 7 (racemate and en-
antiomers) was determined by means of the hot-plate test in the
diabetic neuropathy induced by streptozotocin on mice and by means
of the paw-pressure test in oxaliplatin induced hyperalgesia on rats.
’ RESULTS AND DISCUSSION
The enantiomers of 4 were obtained according to Scheme 2.
Amide 11 was treated with n-BuLi and (R)-2-benzyloxypropio-
nyl chloride to obtain 16 as a 1:1 mixture of diastereoisomers,
which were separated by chromatography, obtaining the single
diastereoisomers 16a and 16b. The chromatographic separation
was not efficient, since 16a and 16b were obtained in 40% and
All the synthesized compounds were able to revert scopola-
mine-induced amnesia, with the exception of 6. The 4-fluorobenze-
nesulfonyl substituent brought the highest activity into the molecules,
since rac-4 and rac-7 show the lowest MED; on the contrary, the
isopropylsulfonyl group was the least effective, since 6 is inactive
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Journal of Medicinal Chemistry
BRIEF ARTICLE
Table 1. Minimal Effective Dose (MED) of the Compounds
against Scopolamine-Induced Amnesia in the Mouse Passive
Avoidance Test, in Comparison with 4-Aminopiperidinesa
administered at 30 mg/kg po was taken as reference. Both
rac-4 (10 mg/kg ip) and rac-7 (3 mg/kg ip) completely reverted
streptozotocin-induced thermal hyperalgesia in the mouse hot plate
test. rac-4 was inactive at a dose of 3 mg/kg ip. Again, no
enantioselectivity is observed for 4, since both optical isomers were
active in this test. On the contrary, there is enantioselectivity for 7:
while (þ)-7 has an efficacy comparable to the racemate, its
levorotatory isomer is devoid of activity at a dose of 3 and 10 mg/
kg. In this model, the activity of 3a is short-lasting, since it reverted
thermal hyperalgesia at 15 min from administration, but after this time
it was devoid of activity.
These results show that in the metabolic model of neuropathy
4 (racemate and enantiomers), rac-7 and (þ)-7 showed an
efficacy comparable to that of pregabalin, the most clinically used
compound. Moreover, they were able to revert hyperalgesia after a
single administration. Several substances, such as aldose reductase
inhibitors, antioxidants, and PKC or PARP inhibitors, can prevent
thermal hyperalgesia in streptozotocin-diabetic rodents only after
repeated administration (see ref 19 and references cited therein).
When compared to other analogues of piracetam, the potency of 4
(racemate and enantiomers), rac-7, and (þ)-7 was similar to that of
nefiracetam and levetiracetam (10 and 20 mg/kg, respectively).20,21
In the same model, these molecules were able to control pain com-
pletely. Moreover, the efficacy of the new compounds is comparable
with that of lacosamide, kinin B1 receptor antagonists, gabapentin,
and oxacarbazepine22,23 and higher than that of amitriptyline.24
Compounds 3a, rac-4 and its enantiomers, and rac-7 were
further evaluated in the rat oxaliplatin-induced hyperalgesia by
means of the paw-pressure test, in comparison with pregabalin
(30 mg/kg po, Figure 1). The compounds were administered ip at
10 mg/kg. While 3a was inactive in this test, both rac-4 and rac-7
were able to revert mechanical hyperalgesia induced by oxaliplatin
with higher efficacy with respect to pregabalin. As far as the
enantiomers of 4 are concerned, some enantioselectivity is observed
in this test, since the reversal of hyperalgesia obtained by (-)-4 is
more effective and longer lasting than that of (þ)-4.
treatment
saline
structure
R
MED (mg/kg)
Δ(s)
82.9
S
25.4∧
66.5**
53.1**
48.1*
53.2**
4 þ S
cis-A
cis-A
cis-A
cis-A
cis-A
trans-A
trans-A
trans-A
trans-A
trans-A
B
SO2C6H4F
SO2C6H4F
SO2C6H4F
COPh
0.1
0.1
0.1
3.0
nac
1.0
1.0
1.0
3.0
10.0
0.01
10
(-)-4 þ S
(þ)-4 þ S
5 þ S
6 þ S
7 þ S
SO2C3H7
SO2C6H4F
SO2C6H4F
SO2C6H4F
COPh
75.8**
79.2**
70.9**
55.4**
65.9**
76.1**
100.7**
75.4**
82.4**
(þ)-7 þ S
(-)-7 þ S
8 þ S
9 þ S
SO2C3H7
SO2C6H4F
COPh
3a þ Sb
3b þ Sb
3c þ Sb
piracetam þ S
B
B
SO2C3H7
1.0
30
a All compounds were dissolved in saline and injected ip 20 min before
training session. Each value represents the mean of 8-18 mice.
Scopolamine (S) was injected immediately after punishment. The scores
of training and retention sessions are reported in Supporting Informa-
tion. * P < 0.05. ** P < 0.01 in comparison with scopolamine-treated
mice. ∧ P < 0.01 in comparison with saline-treated mice. b From ref 17.
c This compound did not revert scopolamine-induced amnesia at doses
up to 10 mg/kg ip.
Chronic neuropathic pain is frequently observed in patients
receiving antitumoral chemotherapy.25 Also, the use of oxalipla-
tin, the third-generation platinum-based chemotherapy in clinical
practice, is significantly limited by the development of a painful
peripheral neuropathy. Treatment with the above-mentioned
antineoplastic drug (and vincristine and paclitaxel) frequently
causes in the oncologic patient the development of neuropathy,26
which is often responsible for the therapy interruption. It is
important to note that there is currently no completely effective
treatment to prevent or reverse this painful condition. Inhibitors
of second messengers implicated in other painful peripheral
neuropathy models (protein kinase A, protein kinase C, nitric
oxide, calcium, and caspase) had no effect in this model after
peripheral administration.27 Antioxidants such as R-lipoic acid
and vitamin C (50-100 mg/kg iv) were able to reduce by
50% the oxaliplatin-induced mechanical hyperalgesia; acetyl-L-
carnitine (at the same doses) showed higher efficacy (75%).
Venlafaxine (7.5 mg/kg) and mexiletine (100 mg/kg) were effective
in this model.27,28 No evidence exists about the activity of piracetam-
like compounds in this kind of hyperalgesia. Here we report the first
evidence that nootropic compounds are effective against this kind of
neuropathy. As a matter of fact, rac-4, (-)-4, and rac-7 were able to
decrease pain sensation with efficacy comparable (80%) with that of
acetyl-L-carnitine,27 at doses 5-10 times lower. On the other hand,
the reference compound pregabalin did not show an analogous
efficacy, relieving pain by only 50%.
and 9 shows a MED of 10 mg/kg. The same trend of activity was
found in the 4-aminopiperidine series (3), where the 4-fluor-
obenzenesulfonyl derivatives were among the most potent
compounds and the isopropylsulfonyl ones the least active.17
The cis-trans configuration is important for the activity of
diastereoisomers 4 and 7, since the cis isomer 4 is more potent
than its trans analogue 7. The same trend is not observed for the
other diastereomeric couples. As a matter of fact, 5 and 8 are
equipotent and 9 shows a MED of 10 mg/kg while its cis isomer 6
is devoid of activity up to this dose. Different from what
happened for the enantiomers of 1, where the R isomer was
3-10 times more potent than the S form,18 no enantioselectivity
is observed in the nootropic activity of 4 and 7.
Overall, these results show that the reduction of conforma-
tional flexibility did not increase the nootropic potency of 4-acet-
ylaminopiperidines, as the sulfonyl derivatives are at least 10-fold less
active than 3a and 3c, while only the benzoyl derivatives 5 and
8 show a modest increase of activity (MED 3 mg/kg) when
compared to 3b (MED 10 mg/kg).17 Nevertheless, this class of
compounds is still 1-2 orders of magnitude more active than
piracetam, whose minimal effective dose in the same test is 30 mg/kg.
Since, as stated in the introduction, several 2-oxopyrrolidine
derivatives show activity in animal models of neuropathic
pain, rac-4, rac-7, their enantiomers, and 3a were tested in a
mouse model of diabetic neuropathy (Table 2). Pregabalin,
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BRIEF ARTICLE
Table 2. Effect of 4 and 7, Their Enantiomers, and 3a on the Hyperalgesia Induced by Streptozotocin in Mouse Hot-Plate Test in
Comparison with Pregabalina
licking latency in mice (s)
after treatment
pretreatment
treatment (mg/kg ip)
before treatment
15 min
30 min
45 min
60 min
saline
STZ
saline
18.2 ( 0.8
10.3 ( 0.7
14.9 ( 1.1
9.2 ( 0.7
17.2 ( 0.9
10.1 ( 0.7
15.8 ( 1.0
9.4 ( 0.7
15.9 ( 1.1
10.7 ( 0.9
16.1 ( 0.9
11.0 ( 1.1
16.5 ( 0.9
9.2 ( 0.8
15.8 ( 0.7
9.9 ( 0.9
14.3 ( 0.9
9.8 ( 0.8
18.1 ( 1.1
9.4 ( 1.3
18.0 ( 1.5
10.1 ( 0.8
16.9 ( 1.1
15.8 ( 1.0*
16.4 ( 1.5
16.5 ( 0.9*
16.8 ( 1.6
16.2 ( 1.2*
16.6 ( 1.8
14.1 ( 1.1*
15.8 ( 1.0
13.7 ( 1.3*
16.4 ( 1.5
9.7 ( 0.9
17.8 ( 1.5
9.3 ( 1.2
18.4 ( 1.6
10.4 ( 1.2
16.3 ( 1.5
17.1 ( 1.6*
17.0 ( 1.6
14.8 ( 0.8∧
17.1 ( 1.5
14.2 ( 1.6∧
17.0 ( 1.3
11.5 ( 1.6
17.4 ( 1.1
10.5 ( 0.9
16.3 ( 1.5
10.0 ( 1.3
15.6 ( 1.5
11.2 ( 0.8
17.0 ( 0.9
15.7 ( 0.9*
saline
saline
STZ
(()-4 (10)
(()-4 (10)
(-)-4 (10)
(-)-4 (10)
(þ)-4 (10)
(þ)-4 (10)
(()-7 (3)
(()-7 (3)
(þ)-7 (3)
(þ)-7 (3)
(-)-7 (3)
(-)-7 (3)
3a
16.3 ( 1.5
16.2 ( 1.2*
17.0 ( 1.3
15.3 ( 1.2*
16.7 ( 1.2
15.7 ( 1.3*
15.9 ( 1.3
14.9 ( 1.2*
16.9 ( 1.5
14.3 ( 1.3*
17.3 ( 0.9
10.4 ( 1.0
16.5 ( 0.9
15.6 ( 1.2*
16.7 ( 1.3
15.3 ( 1.1*
15.8 ( 1.7
17.4 ( 1.4*
16.5 ( 1.2
16.1 ( 1.3*
15.4 ( 1.3
15.3 ( 1.1*
17.2 ( 1.6
12.7 ( 1.4∧
17.0 ( 1.3
12.4 ( 1.0
16.6 ( 1.1
8.8 ( 1.0
saline
STZ
saline
STZ
saline
STZ
saline
STZ
saline
STZ
saline
STZ
15.7 ( 1.2
12.4 ( 1.5
17.1 ( 1.0
16.7 ( 1.3*
16.3 ( 1.4
10.4 ( 1.1
16.1 ( 1.2
15.7 ( 0.9*
3a
saline
STZ
pregabalinb
pregabalinb
a Streptozotocin (STZ), 200 mg/kg ip, was dissolved in citrate buffer and injected 30 days before experiment. Each value represents the mean of at least
10 mice. * P < 0.01. ∧ P < 0.05 in comparison with STZ-treated mice. b Pregabalin was administered at 30 mg/kg po.
In conclusion, the introduction of conformational constraints
into 3a has not increased the nootropic potency in the mouse
passive-avoidance test but still gave compounds 1-2 order of
magnitude more potent than piracetam. The most active compounds
are rac-4 and its enantiomers, which show a minimal effective dose
only 10 times higher than 3a. While geometrical isomerism was
important for activity, the cis 4-fluorobenzenesulfonyl derivative 4
being more active than its trans isomer 7, there is no enantioselectivity
in the nootropic activity of compounds. On the contrary, enantios-
electivity was observed when the compounds were tested on two
models of neuropathy: (þ)-7 (3 mg/kg) is able to revert streptozo-
tocin-induced thermal hyperalgesia in the mouse hot plate test, while
its levorotatory isomer is devoid of activity at the same dose and at 10
mg/kg. As far as 4 is concerned, in the oxaliplatin-induced hyper-
algesia the reversal obtained by (-)-4 is more effective and longer
lasting than that produced by (þ)-4, while in streptozotocin-induced
diabetic neuropathy the two enantiomers have the same efficacy. This
difference may be due to a different pharmacokinetic of the com-
pounds in mouse and rat or to the interaction with a different
biological target. As a matter of fact, as reported above, several
compounds have been shown to be active on one model but not
on the other, indicating that different, yet unknown, mechanisms can
be involved. Nevertheless it is confirmed that these compounds are
promising agents for the treatment of neuropathic pain, including that
induced by chemotherapy.
Figure 1. Effect of compounds (10 mg/kg, single administration, ip) on
’ EXPERIMENTAL SECTION
oxaliplatin-induced hyperalgesia in the rat paw-pressure test in compar-
Chemistry. All melting points were taken on a B€uchi apparatus and
ison with pregabalin (30 mg/kg po). Oxaliplatin (OXA, 2.4 mg/kg) was
administered for 5 consecutive days every week (15 ip injections,
cumulative dose 36 mg/kg). There were 4 rats per group. (A) rac-4,
(þ)-4, and (-)-4; (B) rac-7 and 3a; (/) P < 0.01, (∧) P < 0.05.
are uncorrected. NMR spectra were recorded on a Bruker Avance 400
1
spectrometer (400 MHz for H NMR, 100 MHz for 13C). Chromato-
graphic separations were performed on a silica gel column by gravity
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Journal of Medicinal Chemistry
BRIEF ARTICLE
chromatography (Kieselgel 40, 0.063- 0.200 mm; Merck) or flash
chromatography (Kieselgel 40, 0.040-0.063 mm; Merck). Optical rota-
tion was measured at a concentration of 1 g/100 mL (c = 1), unless
otherwise stated, with a Perkin-Elmer polarimeter (accuracy 0.002°).
Yields are givenafter purification, unlessdifferently stated. Where analyses
are indicated by symbols, the analytical results are within 0.4% of the
theoretical values. When reactions were performed under anhydrous
conditions, the mixtures were maintained under nitrogen. The synthesis
of 4 is described below as representative. The syntheses of all other
compounds are reported in the Supporting Information.
cis 3-(4-Fluorophenylsulfonyl)-3,7-diazabicyclo[4.3.0]nonan
-8-one (4). To a solution of 14 (50 mg) in acetonitrile (15 mL), Et3N
(1.5 equiv) and 4-fluorobenzenesulfonyl chloride (1 equiv) were added. After
being stirred for 2 h at room temperature, the mixture was diluted with
H2O (20 mL), made alkaline with Na2CO3 (10% solution), and extracted
with dichloromethane. After drying and removal of the solvent under vacuum,
the residue was purified by flash chromatography (CHCl3/MeOH 9:1
as eluent), obtaining the title compound in 73% yields, mp 190 °C. Anal.
(C13H15FN2O3S) C, H, N.
(9) For a list of references on the activity of piracetam-like com-
pounds on neuropathic pain see Supporting Information
(10) Romanelli, M. N.; Galeotti, N.; Ghelardini, C.; Manetti, D.;
Martini, E.; Gualtieri, F. Pharmacological characterization of DM232
(unifiram) and DM235 (sunifiram), new potent cognition-enhancers.
CNS Drug Rev. 2006, 12, 39–52.
(11) Raimondi, L.; Ghelardini, C.; Gualtieri, F.; Guandalini, L.;
Manetti, D.; Martini, E.; Romanelli, M. N. DM232 and DM235, Two
Potent Cognition-Enhancers, Increase NO Levels in Rat Adipocytes.
Proceedings of Frontiers in CNS and Oncology Medicinal Chemistry,
Siena, Italy, October 7-9, 2007, 2007; p 47.
(12) Galeotti, N.; Ghelardini, C.; Pittaluga, A.; Pugliese, A. M.;
Bartolini, A.; Manetti, D.; Romanelli, M. N.; Gualtieri, F. AMPA-
receptor activation is involved in the antiamnesic effect of DM232
(unifiram) and DM235 (sunifiram). Naunyn-Schmiedeberg’s Arch. Phar-
macol. 2003, 368, 538–545.
(13) Scapecchi, S.; Martini, E.; Manetti, D.; Ghelardini, C.; Martelli,
C.; Dei, S.; Galeotti, N.; Guandalini, L.; Romanelli, M. N.; Teodori, E.
Structure-activity relationship studies on unifiram (DM232) and
sunifiram (DM235), two novel and potent cognition enhancing drugs.
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hydrolysis with lithium hydroperoxide. Tetrahedron Lett. 1987, 28, 6141–6144.
(15) Misaki, T.; Nagase, R.; Matsumoto, K.; Tanabe, Y. Ti-crossed-
Claisen condensation between carboxylic esters and acid chlorides or
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(16) Jarvik, M. E.; Kopp, R. An improved one-trial passive avoidance
learning situation. Psychol. Rep. 1967, 21, 221–224.
’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic procedures and
b
pharmacological methods. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(17) Manetti, D.; Martini, N.; Ghelardini, C.; Dei, S.; Galeotti, N.;
Guandalini, L.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.; Gualtieri, F.
4-Aminopiperidine derivatives as a new class of potent cognition
enhancing drugs. Bioorg. Med. Chem. Lett. 2003, 13, 2303–2306.
(18) Martini, E.; Ghelardini, C.; Bertucci, C.; Dei, S.; Gualtieri, F.;
Guandalini, L.; Manetti, D.; Scapecchi, S.; Teodori, E.; Romanelli, M. N.
Enantioselective synthesis and preliminary pharmacological evaluation
of the enantiomers of unifiram (DM232), a potent cognition-enhancing
agent. Med. Chem. 2005, 1, 473–480.
Corresponding Author
*Phone: þ39 055 4573691. Fax: þ39 055 4573671.
E-mail: novella.romanelli@unifi.it.
’ ACKNOWLEDGMENT
This work was supported by the Italian MUR (Ministero
dell’Universitꢀa e della Ricerca).
(19) Obrosova, I. G. Diabetic painful and insensate neuropathy: patho-
genesis and potential treatments. Neurotherapeutics 2009, 6, 638–647.
(20) Rashid, M. H.; Ueda, H. Nonopioid and neuropathy-specific
analgesic action of the nootropic drug nefiracetam in mice. J. Pharmacol.
Exp. Ther. 2002, 303, 226–231.
(21) Ozcan, M.; Ayar, A.; Canpolat, S.; Kutlu, S. Antinociceptive
efficacy of levetiracetam in a mice model for painful diabetic neuropathy.
Acta Anaesthesiol. Scand. 2008, 52, 926–930.
’ ABBREVIATIONS USED
LDA, lithium diisopropylamide; MED, minimal effective dose;
PKC, protein kinase C; PARP, poly ADP-ribose polymerase; ee,
enantiomeric excess
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