Abstract
In the scope of a research program aimed at developing new drugs for the treatment of central nervous system diseases, we describe herein the synthesis and pharmacological evaluation of 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one (LQFM180). This compound showed antioxidant activity in two models, electroanalytical assays, and DPPH activity. Moreover, in behavioral tests as the open field test LQFM180 (9.4, 18.8, and 37.6 mg/kg, per oral (p.o.)), we detected anxiolytic-like activity. In the sodium pentobarbital-induced sleep test, LQFM180, in all doses, decreased the latency to sleep and increased sleep duration, indicating central depressant activity; moreover, in the chimney test, LQFM180 did not alter motor activity. LQFM180 (18.8 mg/kg, p.o.) increased the time and number of entries on open arms in the elevated plus maze test, suggesting anxiolytic-like activity, which was reversed by NAN-190 and p-chlorophenylalanine, indicating a role of the serotonergic pathway on this effect. In the forced swimming test, LFQM180 (18.8 mg/kg, p.o.) decreased immobility time, suggesting antidepressant-like activity, which was reversed by monoaminergic antagonists, indicating a role for the serotonergic, noradrenergic, and dopaminergic pathways. Competition binding assays showed that LQFM180 was able to bind to the α1B, 5-HT1A, and D2 receptors, however, within the low micromolar range. We conclude that LQFM180 should be considered as a scaffold for drug candidate development.
Similar content being viewed by others
References
Archer J (1973) Tests for emotionality in rats and mice: a review. Anim Behav 21(2):205–235. https://doi.org/10.1016/S0003-3472(73)80065-X
Asaduzzaman M, Uddin MJ, Kader MA, Alam AH, Rahman AA, Rashid M, Kato K, Tanaka T, Takeda M, Sadik G (2014) In vitro acetylcholinesterase inhibitory activity and the antioxidant properties of Aegle marmelos leaf extract: implications for the treatment of Alzheimer’s disease. Psychogeriatrics 14(1):1–10. https://doi.org/10.1111/psyg.12031
Belzung C, Griebel G (2001) Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res 125(1-2):141–149. https://doi.org/10.1016/S0166-4328(01)00291-1
Beppe GJ, Dongmo AB, Foyet HS, Dimo T, Mihasan M, Hritcu L (2015) The aqueous extract of Albizia adianthifolia leaves attenuates 6-hydroxydopamineinduced anxiety, depression and oxidative stress in rat amygdala. BMC Complement Altern Med 15(1):374. https://doi.org/10.1186/s12906-015-0912-0
Bockaert J, Dumuis A, Bouhelal R, Sebben M, Cory RN (1987) Piperazine derivatives including the putative anxiolytic drugs, buspirone and ipsapirone, are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons. Nauny-Schimiedeberg’s Arch Pharmacol 335(5):588–592. https://doi.org/10.1007/BF00169129
Boissier JR, Dremont C, Robins R, Pagny J (1961) Tentative de pharmacology previsionelle dans de domain des neuroleptique: actions sedative centralle et adrenolytique de la N (dimethoxy-3,4 phenethyl) N (chloro-2 phenyl) piperazine. Arch Int Pharmacodyn Ther 133:29–32
Bouayed J, Rammal H, Soulimani R (2009) Oxidative stress and anxiety: relationship and cellular pathways. Oxidative Med Cell Longev 2(2):63–67. https://doi.org/10.4161/oxim.2.2.7944
Brito AF, Martins JLR, Fajemiroye JO, Galdino PM, De Lima TC, Menegatti R, Costa EA (2012) Central pharmacological activity of a new piperazine derivative: 4- (1-phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester. Life Science 90(23–24):910–916. https://doi.org/10.1016/j.lfs.2012.04.037
Brito AF, Fajemiroye JO, Neri HFS, Silva DM, Silva DPB, Sanz G, Vaz BG, Carvalho FS, Ghedini PC, Lião LM, Menegatti R, Costa EA (2017) Anxiolytic-like effect of 2-(4-((1-phenyl-1 H -pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol is mediated through the benzodiazepine and nicotinic pathways. Chem Biol Drug Des 90(3):432–442. https://doi.org/10.1111/cbdd.12961
Calabrese EJ (2008) An assessment of anxiolytic drug screening tests: hormetic dose responses predominate. Crit Rev Toxicol 38(6):489–542. https://doi.org/10.1080/10408440802014238
Can A, Dao DT, Arad M, Terrillion CE, Piantadosi SC, Gould TD (2012) The mouse forced swim test. J Vis Exp 59(e3638):1–5. https://doi.org/10.3791/3638
Carlini EA, Burgos V (1979) Screening farmacológico de ansiolíticos: Metodologia laboratorial e comparação entre diazepam e clorobenzepam. Rev Assoc Bras Psiquiatr 1:25–31
Carola V, D’Olimpio F, Brunamonti E, Mangia F, Renzi P (2002) Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav Brain Res 134(1-2):49–57. https://doi.org/10.1016/S0166-4328(01)00452-1
Choleris E, Thomas AW, Kavaliers M, Prato FS (2001) A detailed ethological analysis of the mouse open field test: effects of diazepam, diazepoxide and an extremely low frequency pulsed magnetic field. Neurosci Biobehav Rev 25(3):235–260. https://doi.org/10.1016/S0149-7634(01)00011-2
Fajemiroye JO, Galdino PM, Florentino IF, Da Rocha FF, Ghedini PC, Polepally PR, Zjawiony JK, Costa EA (2014) Plurality of anxiety and depression alteration mechanism by oleanolic acid. J Psychopharmacol 28(10):923–934. https://doi.org/10.1177/0269881114536789
Furukawa TA, Salanti G, Atkinson LZ, Leucht S, Ruhe HG, Turner EH, Chaimani A, Ogawa Y, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Suganuma A, Watanabe N, Stockton S, Geddes JR, Cipriani A (2016) Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis. BMJ Open 6(7):1–11. https://doi.org/10.1136/bmjopen-2015-010919
Galdino PM, Nascimento MV, Florentino IF, Lino RC, Fajemiroye JO, Chaibub BA, de Paula JR, de Lima TC, Costa EA (2012) The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice. Prog Neuro-Psychopharmacol Biol Psychiatry 38(2):276–284. https://doi.org/10.1016/j.pnpbp.2012.04.012
Galdino PM, Oliveira DR, Florentino IF, Fajemiroye JO, Valadares MC, Moura SS, Rocha FF, De Lima TC, Costa EA, Menegatti R (2015) Involvement of the monoamine system in antidepressant-like properties of 4-(1-phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester. Life Sci 143:187–193. https://doi.org/10.1016/j.lfs.2015.11.009
Hamon M, Blier P (2013) Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuro-Psychopharmacol Biol Psychiatry 45:54–63. https://doi.org/10.1016/j.pnpbp.2013.04.009
Hassan W, Silva CEB, Mohammadzai IU, Rocha JB (2014) Association of oxidative stress to the genesis of anxiety: implications for possible therapeutic interventions. Curr Neuropharmacol 12(2):120–139. https://doi.org/10.2174/1570159X11666131120232135
Hillhouse TM, Porter JH (2015) A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 23(1):1–21. https://doi.org/10.1037/a0038550
Hritcu L, Noumedem JA, Cioanca O, Hancianu M, Postu P, Mihasan M (2015) Anxiolytic and antidepressant profile of the methanolic extract of Piper nigrum fruits in beta-amyloid (1–42) rat model of Alzheimer’s disease. Behav Brain Funct 11(1):13. https://doi.org/10.1186/s12993-015-0059-7
Kimura M, Masuda T, Yamada K, Mitani M, Kubota N, Kawakatsu N, Kishii K, Inazu M, Kiuchi Y, Oguchi K, Namiki T (2003) Synthesis of novel diphenyl piperazine derivatives and their activities as inhibitors of dopamine uptake in the central nervous system. Bioorg Med Chem 11(8):1621–1630. https://doi.org/10.1016/S0968-0896(03)00061-0
Kornum BR, Licht CL, Weikop P, Knudsen GM, Aznar S (2006) Central serotonin depletion affects rat brain areas differently: a qualitative and quantitative comparison between different treatment schemes. Neurosci Lett 392(1–2):129–134. https://doi.org/10.1016/j.neulet.2005.09.013
Kubacka M, Mogilski S, Bednarski M, Nowinski L, Dudek M, Zmudzka E, Siwek A, Waszkielewicz AM, Marona H, Satala G, Bojarski A, Filipek B, Pytka K (2016) Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action. Pharmacol Biochem Behav 141:28–41. https://doi.org/10.1016/j.pbb.2015.11.013
Lister RG (1987) The use of a plus maze to measure anxiety in the mouse. Psychopharmacology 92(2):180–185
Mayorga AJ, Dalvi A, Page ME, Zimov-Levinson S, Hen R, Lucki I (2001) Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J Pharmacol Exp Ther 298(3):1101–1107
Mokrosz JL, Pietrasiewicz M, Duszynska B, Cegla MT (1992) Structure-activity relationship studies of central nervous system agents. 5. Effect of the hydrocarbon chain on the affinity of 4-substituted 1-(3-chlorophenyl) piperazine for 5-HT1A receptor site. J Med Chem 35(13):2369–2374. https://doi.org/10.1021/jm00091a004
Mork A, Pehrson A, Brennum LT, Nielsen SM, Zhong H, Lassen AB, Miller S, Westrich L, Boyle NJ, Sanchez C, Fischer CW, Liebenberg N, Wegener G, Bundgaard C, Hogg S, Bang-Andersen B, Stensbol TB (2012) Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther 340(3):666–675. https://doi.org/10.1124/jpet.111.189068
Nascimento-Viana JB, Carvalho AR, Nasciutti LE, Alcántra-Hernández R, Chagas-Silva F, Souza PAR, Romeiro LAS, Garcia-Sáinz JA, Noel F, Silva CLM (2016) New multi-target antagonists of α1A-, α1D-adrenoceptors and 5-HT1A receptors reduce human hyperplastic prostate cell growth and the increase of intraurethral pressure. J Pharmacol Exp Ther 356(1):212–222. https://doi.org/10.1124/jpet.115.227066
Neves G, Menegatti R, Antonio CB, Grazziottin LR, Vieira RO, Rates SM, Noel F, Barreiro EJ, Fraga CA (2010) Searching for multi-target antipsychotics: discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors. Bioorg Med Chem 18(5):1925–1935. https://doi.org/10.1016/j.bmc.2010.01.040
Novas M, Wolfaman C, Medina JH, De Robertis E (1988) Proconvulsant and ‘anxiogenic’ effects of n-butyl B carboline-3-carboxylate, an endogenous BZD binding inhibitor from brain. Pharmacol Biochem Behav 30(2):331–336. https://doi.org/10.1016/0091-3057(88)90463-7
O’Leary OF, Bechtholt AJ, Crowley JJ, Hill TE, Page ME, Lucki I (2007) Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology 192(3):357–371. https://doi.org/10.1007/s00213-007-0728-9
Orjales A, Alonso-Cires L, Labeaga L, Corcóstegui R (1995) New (2-methoxyphenyl) piperazine derivatives as 5-HT1A receptor ligands with reduced α1-adrenergic activity. Synthesis and structure-affinity relationships. J Med Chem 38(8):1273–1277. https://doi.org/10.1021/jm00008a005
Overstreet DH, Wegener G (2013) The flinders sensitive line rat model of depression—25 years and still producing. Pharmacol Rev 65(1):143–155. https://doi.org/10.1124/pr.111.005397
Oyemitan IA, Olayera OA, Alabi A, Abass LA, Elusiyan CA, Oyedeji AO, Akanmu MA (2015) Psychoneuropharmacological activities and chemical composition of essential oil of fresh fruits of Piper guineense (Piperaceae) in mice. J Ethnopharmacol 166:240–209. https://doi.org/10.1016/j.jep.2015.03.004
Park HR, Lee H, Park H, Cho WK, Ma JY (2016) Fermented Sipjeondaebo-tang alleviates memory deficits and loss of hippocampal neurogenesis in scopolamine-induced amnesia in mice. Sci Rep 6(22405):2016. https://doi.org/10.1038/srep22405
Pawlak CR, Karrenbauer BD, Schneider P, Ho YJ (2012) The elevated plus-maze test: differential psychopharmacology of anxiety-related behavior. Emot Rev 4(1):98–115. https://doi.org/10.1177/1754073911421374
Pellow S, Chopin P, File S, Briley M (1985) Validation of open-closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167. https://doi.org/10.1016/0165-0270(85)90031-7
Pesarico AP, Sampaio TB, Stangherlin EC, Mantovani AC, Zeni G, Nogueira CW (2014) The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems. Prog Neuro-Psychopharmacol Biol Psychiatry 54:179–186. https://doi.org/10.1016/j.pnpbp.2014.06.001
Petit-Demouliere B, Chenu F, Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology 177(3):245–255. https://doi.org/10.1007/s00213-004-2048-7
Prinssen EP, Colpaert FC, Koek W. 5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy. Eur J Pharmacol. 2002 Oct 25;453(2-3):217–21
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463(1-3):3–33. https://doi.org/10.1016/S0014-2999(03)01272-X
Rodrigues O.R.L. (2015) Avaliação farmacológica no sistema nervoso central de um novo derivado piperazínico LQFM 104. 92 f. Dissertation (Master in Pharmaceutical Sciences) Faculty of Pharmacy. Federal University of Goiás
Salim S (2014) Oxidative stress and psychological disorders. Curr Neuropharmacol 12(2):140–147. https://doi.org/10.2174/1570159X11666131120230309
Salim S (2017) Oxidative stress and the central nervous system. J Pharmacol Exp Ther 360(1):201–205. https://doi.org/10.1124/jpet.116.237503
Siegel PS (1946) A simple electronic device for the measurement of gross bodily activity of small animals. Aust J Psychol 21(2):227–236. https://doi.org/10.1080/00223980.1946.9917283
Talarek S, Orzelska-Gorka J, Listos J, Serefko A, Poleszak E, Fidecka S (2016) Effects of NMDA antagonists on the development and expression of tolerance to diazepam-induced motor impairment in mice. Pharmacol Biochem Behav 142:42–47. https://doi.org/10.1016/j.pbb.2015.12.009
Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J Vis Exp 91(e51785):1–7. https://doi.org/10.3791/51785
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328. https://doi.org/10.1038/nprot.2007.44
Waszkielewicz AM, Pytka K, Rapacz A, Welna E, Jarzyna M, Satala G, Bojarski A, Sapa J, Zmudzki P, Filipek B, Marona H (2015) Synthesis and evaluation of antidepressant-like activity of some 4-substituted 1-(2-methoxyphenyl) piperazine derivatives. Chem Biol Drug Des 85(3):326–335. https://doi.org/10.1111/cbdd.12394
Xu Y, Wang C, Klabnik JJ, O’Donnell JM (2014) Novel therapeutic targets in depression and anxiety: antioxidants as a candidate treatment. Curr Neuropharmacol 12(2):108–119. https://doi.org/10.2174/1570159X11666131120231448
Yehye WA, Rahman NA, Ariffin A, Hamid SBA, Alhadi AA, Kadir FA, Yaeghoobi M (2015) Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): a review. Eur J Med Chem 101:295–312. https://doi.org/10.1016/j.ejmech.2015.06.026
Zafir A, Ara A, Banu N (2009) In vivo antioxidant status: a putative target of antidepressant action. Prog Neuro-Psychopharmacol Biol Psychiatry 33(2):220–208. https://doi.org/10.1016/j.pnpbp.2008.11.010
Zagorska A, Kolaczkowski M, Bucki A, Siwek A, Kazek G, Satala G, Bojarski AJ, Partyka A, Wesolowska A, Pawlowski M (2015) Structure activity relationships and molecular studies of novel arylpiperazinylalkyl purine-2,4-diones and purine-2,4,8-triones with antidepressant and anxiolytic-like activity. Eur J Med Chem 97:142–154. https://doi.org/10.1016/j.ejmech.2015.04.046
Funding
The authors are grateful to FAPEG, FAPERJ, CAPES, and CNPq for financial support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical approval
All experiments were carried out according to the Ethical Principles in Animal Research as adopted by the Brazilian Society of Laboratory Animal Science and were approved by the “Comissão de Ética no Uso de Animais” of the Federal University of Goiás-Brazil (no. 021/13) or Federal University of Rio de Janeiro, Brazil (no. DFBCICB021).
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Brito, A.F., Braga, P.C.C.S., Moreira, L.K.S. et al. A new piperazine derivative: 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one with antioxidant and central activity. Naunyn-Schmiedeberg's Arch Pharmacol 391, 255–269 (2018). https://doi.org/10.1007/s00210-017-1451-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-017-1451-7