Biotransformation of LASSBio-579 and pharmacological evaluation of p-hydroxylated metabolite a N-phenylpiperazine antipsychotic lead compound.
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).
Laboratório de Bioconversão, LabMol and Laboratório de Química Farmacêutica Medicinal, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
Tatiana F
TF
Gomes
Thais E T
TE
Pompeu
Daniel A
DA
Rodrigues
François
F
Noël
Ricardo
R
Menegatti
Carolina H
CH
Andrade
José R
JR
Sabino
Eric S
ES
Gil
Teresa
T
Dalla Costa
Andresa H
AH
Betti
Camila B
CB
Antonio
Stela M K
SM
Rates
Carlos A M
CA
Fraga
Eliezer J
EJ
Barreiro
Valéria
V
de Oliveira
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D007854:Lead / Q000737:chemistry*; D008297:Male; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; C518328:LASSBio-579; D009942:Organometallic Compounds; D010879:Piperazines; D050638:Receptors, Dopamine D4; D007854:Lead; C031503:phenylpiperazine