LASSBio-1422: a new molecular scaffold with efficacy in animal models of schizophrenia and disorders of attention and cognition

Abstract

Aiming to identify new antipsychotic lead-compounds, our group has been working on the design and synthesis of new N-phenylpiperazine derivatives. Here, we characterized LASSBio-1422 as a pharmacological prototype of this chemical series. Adult male Wistar rats and CF1 mice were used for in-vitro and in-vivo assays, respectively. LASSBio-1422 [1 and 5 mg/kg, postoperatively (p.o.)] inhibited apomorphine-induced climbing as well as ketamine-induced hyperlocomotion (1 and 5 mg/kg, p.o.), animal models predictive of efficacy on positive symptoms. Furthermore, LASSBio-1422 (5 mg/kg, p.o.) prevented the prepulse impairment induced by apomorphine, (±)-2,5-dimethoxy-4-iodoamphetamine, and ketamine, as well as the memory impairment induced by ketamine in the novel object-recognition task at the acquisition, consolidation, and retrieval phases of memory formation. Potential extrapyramidal side-effects and sedation were assessed by catatonia, rota-rod, locomotion, and barbiturate sleeping time, and LASSBio-1422 (15 mg/kg, p.o.) did not affect any of the parameters observed. Binding assays showed that LASSBio-1422 has a binding profile different from the known atypical antipsychotic drugs: it does not bind to AMPA, kainate, N-methyl-D-aspartate, glicine, and mGluR2 receptors and has low or negligible affinity for D1, D2, and 5-HT2A/C receptors, but high affinity for D4 receptors (Ki=0.076 µmol/l) and, to a lesser extent, for 5-HT1A receptors (Ki=0.493 µmol/l). The antagonist action of LASSBio-1422 at D4 receptors was assessed through the classical GTP-shift assay. In conclusion, LASSBio-1422 is effective in rodent models of positive and cognitive symptoms of schizophrenia and its ability to bind to D4 and 5-HT1A receptors may at least in part explain its effects in these animal models.

Animal models for the evaluation of antipsychotic agents

“…In another study, clozapine and LASSBio-1422 reversed the deficit only at the lowest pre-pulse stimulus while haloperidol was ineffective at all pre-pulse intensities. This model can be used to identify anti-serotoninergic activity of the test drug [20,23].…”

Advantages and Limitations of Animal Schizophrenia Models

“…Administration of DOI induces head-twitch response (HTR), resembling positive schizophrenia symptoms (particularly hallucinations), and this effect is blocked by antipsychotic agents [ 34 ]. Moreover, DOI disrupts PPI [ 35 , 36 ], however, without changes in locomotor activity [ 37 ]. On a molecular level, DOI induces an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons [ 38 , 39 ].…”