Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579

• We report an optimization of our antipsychotic lead compound LASSBio-579.
• Five new N-phenylpiperazines were synthesized using an homologation strategy.
• A 10-fold increase in affinity for the 5-HT2A receptor was succeeded (LASSBio-1635).
• A GTP-shift assay showed that LASSBio-1635 is an antagonist of the 5-HT2A receptor.
• LASSBio-1635 was active in two mice models of schizophrenia positive symptoms.

In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT2A receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3–10-fold for the 5-HT2A receptor, with no relevant change in the affinity for the D2-like and 5-HT1A receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5-HT2A receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound.

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