916
A.F. de Brito et al. / Life Sciences 90 (2012) 910–916
Chen SW, Wang WJ, Li WJ, Li YL, Huang YN, Liang X. Anxiolytic-like effect of asiatico-
side in mice. Pharmacol Biochem Behav 2006;85:339–44.
Clement Y, Chapouthier G. Biological bases of anxiety. Neurosci Biobehav Rev 1998;22:
623–33.
Crawley JN, Goodwin FK. Preliminary report of a simple animal behaviour for the anxi-
olytic effects of benzodiazepines. Pharmacol Biochem Behav 1980;13:167–70.
Dunham NW, Miya TS. A note on a simple apparatus for detecting neurological deficit
in rats and mice. J Am Pharm Assoc 1957;46:208–10.
Farkas S, Berzsenyi P, Karpati E, Kocsis P, Tarnawa I. Simple pharmacological test bat-
tery to assess efficacy and side effect profile of centrally acting muscle relaxant
drugs. J Pharmacol Toxicol Methods 2005;52:264–73.
Finar I, Hurlock R. The preparation of some trinitrophenylpyrazoles. J Chem Soc 1957:
3024–7.
Gray DL, Xu W, Campbell BM, Dounay AB, Barta N, Boroski S, et al. Discovery and phar-
macological characterization of aryl piperazine and piperidine ethers as dual acting
norepinephrine reuptake inhibitors and 5-HT1A partial agonists. Bioorg Med Chem
Lett 2009;19:6604–7.
Han H, Ma Y, Eun JSE, Li R, Hong JT, Lee MK, et al. Anxiolytic effects of sanjoinine A iso-
lated from Zizyphi spinosi Semen: possible involvement of GABAergic transmission.
Pharmacol Biochem Behav 2009;92:206–13.
Hoog S. A review of the validity and variability of the elevated plus-maze as an animal
model of anxiety. Pharmacol Biochem Behav 1996;54:21–30.
Johansson A, Abrahamsson M, Magnuson A, Huang P, Martensson J, Styring S, et al. Syn-
thesis and photophysics of one mononuclear Mn(III) and one dinuclear Mn(III, III)
complex covalently linked to a ruthenium(II) tris(bipyridyl) complex. Inorg Chem
2003;42:7502–11.
Katzman MA. Aripiprazole: a clinical review of its use for the treatment of anxiety dis-
orders and anxiety as a comorbidity in mental illness. J Affect Disord 2011;128S1:
S11–20.
Khatri M, Rai SK, Alam S, Vij A, Tiwari M. Synthesis and pharmacological evaluation of
new arylpiperazines N-{4-[4-(aryl) piperazine-1-yl]-phenyl}-amine derivatives:
putative role of 5-HT1A receptors. Bioorg Med Chem 2009;17:1890–7.
Lalehzari A, Desper J, Levy CJ. Double-stranded monohelical complexes from an un-
symmetrical chiral Schiff-base ligand. Inorg Chem 2008;47:1120–6.
Lindoy LF, Meehan GV, Svenstrup N. Mono- and diformylation of 4-substituted phe-
nols: A new application of the duff reaction. Synthesis 1998;7:1029–32.
Lister RG. The use of a plus maze to measure anxiety in the mouse. Psychopharmacol-
ogy 1987;92:180–5.
putative underlying mechanism of action involved in LQFM008
anxiolytic-like activity.
In the study of mechanism of action, we proposed to investigate the
involvement of the benzodiazepine site and the serotonin receptor type
1A. Pre-treatment with flumazenil (benzodiazepine antagonist) did not
antagonize the LQFM008 anxiolytic-like activity in the elevated plus
maze test, hence, excluding the benzodiazepine site in the LQFM008 ef-
fect. The pre-treatment with NAN-190 (a 5-HT1A antagonist) antago-
nized the LQFM008 anxiolytic-like effect, when compared with the
results observed after the treatment with LQFM008, thus, suggesting
the participation of 5-HT1A receptor in LQFM008 activity.
Although clinically the anxiolytic activity of 5HT1A agonists that act
on the somatodendritic autoreceptors in the dorsal raphe nucleus of
midbrain raphe is a consequence of their desensitization during repeat-
ed treatment over several days. Meanwhile, in rodent experimental
models, this anxiolytic activity can be observed after an acute treat-
ment, as observed in this study and, by Cao and Rodgers (1997),
Young and Johnson (1991) and Peng et al. (2004) that demonstrated
the anxiolytic-like activity of buspirone, a 5-HT1A partial agonist, in
the elevated plus maze test and light–dark box tests after an acute treat-
ment. Moreover, several reports in the literature have associated
anxiolytic-like activity of piperazine derivatives to the involvement of
serotoninergic pathway (Avgustinovich et al., 2003; Bojarski et al.,
2006; Gray et al., 2009; Khatri et al., 2009; Paluchowska et al., 2007).
This result as a matter of fact does not necessarily exclude the in-
volvement of other binding site of GABA and other neurotransmitters
in LQFM008 anxiolytic-like effect. Future research will be targeted at
elucidating the interaction of this compound with monoamine reup-
take and metabolism.
Luo G, Mattson GK, Bruce MA, Wong H, Murphy BJ, Longhi D, et al. Isosteric N-
arylpiperazine replacements in a series of dihydropyridine NPY1 receptor antago-
nists. Bioorg Med Chem Lett 2004;14:5975–8.
Conclusions
Malone MH. Pharmacological approaches to natural product, screening and evaluation.
In: Wagner H, Wolff P, editors. New natural products and plant drugs with pharma-
cological, biological, or therapeutical activity. Berlin: Springer-Verlag; 1977. p. 23–53.
Menegatti R, Cunha AC, Ferreira VF, Perreira EFR, Nabawi AE, Eldefrawi AT, et al. De-
sign, synthesis and pharmacological profile of novel dopamine D2 receptor ligands.
Bioorg Med Chem 2003;11:4807–13.
Neves G, Menegatti R, Antonio CB, Grazziottin LR, Vieira RO, Rates SMK, et al. Searching for
multi-target antipsychotics: discovery of orally active heterocyclic N-phenylpiperazine
ligands of D2-like and 5-HT1A receptors. Bioorg Med Chem 2010;18:1925–35.
Novas ML, Wolfman C, Medina JH, De Robertis E. Proconvulsant and anxiogenic effects
of n-butyl-β-carboline-3-carboxilate on endogenous benzodiazepine binding in-
hibitor from brain. Pharmacol Biochem Behav 1988;30:331–6.
The compound LQFM008 is a new piperazine derivative that has
an anxiolytic-like activity in different animal models without
compromising motor activity, and this activity seems to involve the
participation of 5-HT1A receptors.
Conflict of interest statement
There were no conflicts of interest in carrying out this work.
Paluchowska MH, Bugno R, Duszynska B, Tatarcynska E, Nikiforuk A, Lenda T, et al. The
influence of modifications in imide fragment structure on 5-HT1A and 5-HT7 re-
ceptor affinity and in vivo pharmacological properties of somo new 1-(m-trifluor-
omethylphenyl)piperazines. Bioorg Med Chem 2007;15:7116–25.
Papakostas GI, Fava M. A meta-analysis of clinical trials comparing the serotonin (5-
HT)-2 receptor antagonists trazodone and nefazodone with selective serotonin re-
uptake inhibitors for the treatment of major depressive disorder. Eur Psychiatry
2007;22:444–7.
Acknowledgments
The authors are grateful to FUNAPE/UFG, FAPEG, PROCAD/CAPES
and CNPq for financial support.
References
Pellow S, Chopin P, File S, Briley M. Validation of open-closed arm entries in an elevated
plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985;14:149–67.
Peng WH, Wu CR, Chen CS, Chen CF, Leu ZC, Hsieh MT. Anxiolytic effect of berberine on
exploratory activity of the mouse in two experimental anxiety models: interaction
with drugs acting at 5-HT receptors. Life Sci 2004;75:2451–62.
Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on
anxiety-like behaviors: a review. Eur J Pharmacol 2003;463:3-33.
Rex A, Voigt JP, Voits M, Fink H. Pharmacological evaluation of a modified open-field
test sensitive to anxiolytic drugs. Pharmacol Biochem Behav 1998;59:677–83.
Sadashiva CT, Chandra NS, Ponnappa KC, Gowda TV, Rangappa KS. Synthesis and effi-
cacy of 1-[bis(4-fluorophenyl)-methyl]piperazine derivatives for acetylcholines-
Andreatini R, Lacerda RB, Filho DZ. Tratamento farmacológico do transtorno de ansie-
dade generalizada: perspectivas futuras. Rev Bras Psiquiatr 2001;23:233–42.
Angrini M, Leslie JC, Shephard RA. Effects of propranolol, buspirone, pCPA, reserpine,
and chlordiazepoxide on open-field behavior. Pharmacol Biochem Behav
1998;59:387–97.
Archer J. Tests for emotionality in rats and mice: a review. Anim Behav 1973;21:
205–35.
Avgustinovich DF, Alekseyenko OV, Koryakina LA. Effects of chronic treatment with
ipsapirone and buspirone on the C57BL/6J strain mice under social stress. Life Sci
2003;72:1437–44.
Bojarski AJ, Paluchowska MH, Duszynska B, Bugno R, Klodzinska A, Tatarczynska E,
et al. Structure-intrinsic activity relationship studies in the group of 1-
imido/amido substituted 4-(4-arylpiperazin-1-yl) cyclohexane derivatives; new,
potent 5-HT1A receptor agents with anxiolytic-like activity. Bioorg Med Chem
2006;14:1391–402.
Cao BJ, Rodgers RJ. Comparative behavioural profiles of buspirone and its metabolite
1-(2-pyrimidinyl)-piperazine (1-PP) in the murine elevated plus-maze. Neuro-
pharmacology 1997;36:1089–97.
Carlini EA, Burgos V. Screening farmacológico de ansiolíticos: Metodologia laboratorial
e comparação entre diazepam e clorobenzepam. Rev Assoc Bras Psiquiatr 1979;1:
25–31.
Carlini EA, Constar JDP, Silva-Filho AR, Silveira-Filho NG, Frochtengarten MI, Bueno
OVA. Pharmacology of lemon-grass (Cymbopogon citratus Stapf). Effects of teas
prepared from leaves on laboratory-animals. J Ethnopharmacol 1986;17:37–64.
terase inhibition, as a stimulant of central cholinergic neurotransmission in
Alzheimer's disease. Bioorg Med Chem Lett 2006;16:3932–6.
Schmitt RLS. Revisão sistemática e meta-análise do uso de antidepressivos no transtorno de
ansiedade generalizada. Dissertação (Mestrado em Ciências Médicas — Psiquiatria) —
Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, 2003.
Siegel PS. A simple electronic device for the measurement of gross bodily activity of
small animals. J Psychol 1946;21:227–36.
Sokal RR, Rohlf FJ. Biometry: the principles and practice of statistics in biological re-
search. 2nd ed. Nova York: WH Feeman & Co; 1981.
Young R, Johnson DN. Comparison of routes of administration and time course effects
of zacopride and buspirone in mice using an automated light/dark test. Pharmacol
Biochem Behav 1991;40:733–7.
Yu HS, Lee SY, Jang CG. Involvement of 5-HT1A and GABAA receptors in the anxiolytic-
like effects of Cinnamomum cassia in mice. Pharmacol Biochem Behav 2007;87:16.