No abstract

The primary aims were to study the metabolism in rats and to determine the biological levels after one oral developmentally toxic dose of N-methyl-2-pyrrolidone (NMP), a widely used industrial chemical. Non-pregnant female Sprague-Dawley rats were given an oral single dose of either a non-toxic dose of 125 mg NMP/kg (group 1) by gavage or a developmentally toxic dose of 500 mg/kg (group 2). Blood plasma (7 rats per time point) and urine (10 rats per time point) were sampled up to 72h after administration and analyzed using mass spectrometry. In both plasma and urine NMP, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP), N-methylsuccinimide and 2-hydroxy-N-methylsuccinimide (2-HMSI) and 2-pyrrolidone (2-P) were identified. In urine 48% of the administered dose was recovered as 5-HNMP and 2-5% as 2-HMSI. The total recovery in urine was 53-59%. The peak concentrations for NMP in plasma were 1.2 and 6.9 mmol/l, 0.42 and 0.76 mmol/l for 5-HNMP, 0.07 and 0.31 mmol/l for MSI and for 2-HMSI the concentrations were 0.02 and 0.05 mmol/l for group 1 and 2, respectively. In summary, the same metabolites were found in rats as in humans and the biological levels were reported for NMP and its metabolites after oral exposure to a developmentally toxic dose and one non-toxic dose of NMP.

Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3',5'-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus (p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions.

No abstract

No abstract