New insights into pharmacological profile of LASSBio-579, a multi-target N-phenylpiperazine derivative active on animal models of schizophrenia

Neves, Gilda; Antonio, Camila B.; Betti, Andresa Heemann; Pranke, Mariana A.; Fraga, Carlos A.M.; Barreiro, Eliezer J.; Noël, François; Rates, Stela Maris Kuze

doi:10.1016/j.bbr.2012.09.016

Cited by 23 publications

(16 citation statements)

References 47 publications

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“…Briefly, oral administration of LASSBio-579 in mice inhibited the apomorphine-induced climbing, ketamine-induced hyperlocomotion and deficit of prepulse inhibition of acoustic startle reflex induced by apomorphine, (±)-DOI and ketamine (Neves et al, 2013). Our binding studies defined LASSBio-579 as a moderate affinity ligand of D 2 -like/D 4 /5-HT 1A receptors (K i values around 0.2-0.4 μM) with low affinity for the 5-HT 2A receptor (K i around 7 μM) and other receptors putatively involved in atypicality (Neves et al, 2010;Pompeu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor

Pompeu

Monte

Bosier

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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In an attempt to better understand the molecular mechanism of action of the antipsychotic lead LASSBio-579 and of its main metabolite LQFM 037, the aim of this work was to evaluate their intrinsic activity and binding kinetics at the dopamine D2 receptor. In transfected HEK cells expressing the D2L receptor under an inducible promoter, LASSBio-579 and LQFM 037, but not clozapine, behaved as weak partial agonists in [(35)S]-GTPγS binding assays performed in optimized conditions previously shown to evidence the partial agonist profile of aripiprazole. Besides, data obtained in radioligand competition assays on rat striatal membranes suggested a rapid association to and dissociation from the D2-like receptors. Using the kinetic rate index based on the strategy of the dual-point competition association assay, we showed that our compounds share a similar kinetic profile with clozapine, distinct from the typical antipsychotic haloperidol. These two characteristics could contribute to the atypical-like profile observed after administration of LASSBio-579 to rodents, in models of positive and negative symptoms of schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor

Pompeu

Monte

Bosier

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…The antidepressant effect of sub-anesthetic doses of ketamine has been demonstrated in several studies in mice (Maeng et al 2008, Popik et al 2008, Silva et al 2010, rats (Akinfiresoye and Tizabi 2013, Fraga et al 2013, Garcia et al 2008a, b, 2009, Li et al 2010, Parise et al 2013, Popik et al 2008, Reus et al 2011, Tizabi et al 2012, Yang et al 2012) and humans (Maeng and Zarate 2007, Rot et al 2010, Zarate et al 2006, and the investigation of its mechanism of action or even the involvement of active metabolites is an active field of research (Li et al 2010, Newport et al 2015, Zanos et al 2016). Contrary to our results, there are few works successfully describing the use of ketamine repeated treatment to mimic schizophrenia negative symptoms in the forced swimming.…”

Section: Discussionmentioning

confidence: 94%

“…This dual effect of this drug has been discussed elsewhere (Fraga et al 2013, Neill et al 2014. Some authors propose that it can be 1664 GILDA NEVES et al attributed to the blockade of NMDAR composed by different patterns of subunits (GluN2a vs. GluN2b) (Jiménez-Sánchez et al 2014) while others attribute it to an increase in glutamate efflux in cortical areas and a consequent activation of AMPA receptors leading to modulation of non-classical signaling pathways such as the GSK3/b-catenin (Maeng et al 2008, Beurel et al 2016.…”

Section: Immobility Behavior For Modeling Schizophrenias 1663mentioning

confidence: 95%

“…This drug is able to induce hyperlocomotion, stereotypy, as well as deficits in attentional and memory processes in rodents (Chan et al 2008, Imre et al 2006, Neves et al 2013, Pietersen et al 2007, Pitsikas et al 2008, Rodvelt et al 2008, Wang et al 2006). Becker et al (2003 and Becker and Grescksch (2004) showed that a sub-anesthetic dose of ketamine (30 mg/kg/day i.p.)…”

Section: Introductionmentioning

confidence: 99%

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Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Neves

Borsoi

Antonio

et al. 2017

An. Acad. Bras. Ciênc.

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Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine subanesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

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“…A few compounds, i.e., 1-[1-(4-chlorophenyl)-1H-pyrazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-579, 23 , Figure 13 ), 1-phenyl-4-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-piperazine (LASSBio-580) and 1-[1-(4-chlorophenyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-581) were selected based on potential antipsychotic activity. It was found that LASSBio-579 is the most promising of the three compounds, thanks to its affinity to both dopamine and serotonin receptors, in particular agonist activity at 5-HT 1A receptor [ 131 ]. Thus, this multi-target compound was active in animal models of psychosis and reversed the catalepsy induced by WAY 100,635, Furthermore, co-administration of sub-effective doses of LASSBio-579 with sub-effective doses of clozapine or haloperidol prevented apomorphine-induced climbing without induction of catalepsy [ 131 ].…”

Section: Multi-target Compounds To Treat Schizophreniamentioning

confidence: 99%

Multi-Target Approach for Drug Discovery against Schizophrenia

Kondej

Stępnicki

Kaczor

2018

IJMS

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Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D2 receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of α7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds.

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New insights into pharmacological profile of LASSBio-579, a multi-target N-phenylpiperazine derivative active on animal models of schizophrenia

Cited by 23 publications

References 47 publications

Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor

Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Multi-Target Approach for Drug Discovery against Schizophrenia

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