Biotransformation of LASSBio-579 and pharmacological evaluation of p-hydroxylated metabolite a N-phenylpiperazine antipsychotic lead compound.

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Gomes TF, Pompeu TE, Rodrigues DA, Noel F, Menegatti R, Andrade CH, Sabino JR, Gil ES, Dalla Costa T, Betti AH, Antonio CB, Rates SM, Fraga CA, Barreiro EJ, de Oliveira V

Biotransformation of LASSBio-579 and pharmacological evaluation of p-hydroxylated metabolite a N-phenylpiperazine antipsychotic lead compound.

Eur J Med Chem. 2013 Apr;62:214-21. doi: 10.1016/j.ejmech.2012.08.011. Epub 2012 Aug 20.

PubMed ID

23353740 [ View in PubMed

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Abstract

Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1-(4-chlorophenyl)-1H-4pyrazolylmethyl] phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Clozapine	5-hydroxytryptamine receptor 2C	Ki (nM)	24	N/A	N/A	Details
Clozapine	Dopamine D4 receptor	Ki (nM)	60	N/A	N/A	Details