Distribution of the methylpiperazinopyridobenzoxazepine derivative JL13, a potential antipsychotic, in rat brain

Abstract

The brain uptake and distribution of the potential antipsychotic 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3][1,5]benzoxazepine fumarate (JL13) was examined in rats after neuropharmacologically active doses. Plasma and brain concentrations of the compound were measured by reversed-phase HPLC with UV detection (210 nm). Clozapine was used as an internal standard. After an intraperitoneal dose of 10 mg kg(-1), the compound attained mean maximum plasma concentrations within 5 min of dosing, then declined with a mean elimination half-life of approximately 1 h. It rapidly crossed the blood-brain barrier and equilibrated with plasma, achieving mean maximum concentrations and area under the curve approximately 20-times those in plasma, with slight regional differences. Disappearance from whole brain almost paralleled its disappearance from plasma. There was a linear relationship between JL13 concentrations in plasma and brain regions, and in all tissues the concentrations of the compound increased almost linearly with the dose over the range of 5-20 mg kg(-1). It thus appears that JL13 brain pharmacokinetics parallels that in plasma, and that plasma concentrations accurately predict brain concentrations in rats.

JL 13, An Atypical Antipsychotic: A Preclinical Review

“…After intraperitoneal injection of JL 13 (5 to 20 mg/kg), plasma and striatum concentrations increased in parallel and in a linear way (31). Distribution of JL 13 in selected regions of the rat brain (prefrontal cortex, nucleus accumbens, striatum) after intraperitoneal doses of 5 to 20 mg/kg indicated a dose-dependent increase in these three regions.…”

Environmentally Benign One‐pot Synthesis of Benzo‐Fused Seven‐Membered Heterocyclic Compounds Using UiO‐66 Metal‐Organic Framework as Efficient and Reusable Catalyst

“…Benzoxazepines and benzodiazepines are benzo-fused sevenmembered heterocyclic compounds constituting two important classes of building blocks in drug discovery due to a wide range of their biological activities such as anti-psychotic, [1][2][3][4] anti-convulsant, [5][6][7][8] anti-cancer, [9][10][11] anti-HIV1, [12][13] antibacterial, [14] and progesterone receptor agonists. [15] Representative examples of some biologically important benzoxazepines and benzodiazepines are illustrated in Scheme 1.…”