Assessing the emetic potential of PDE4 inhibitors in rats.

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.

Substituted furans as inhibitors of the PDE4 enzyme.

The synthesis and in vitro activity of a series of substituted furans as a novel structural class of PDE4 inhibitors is described. Comparison of emetic threshold with known PDE4 inhibitors is presented.

In vitro and in vivo biotransformations of the potent leukotriene D4 antagonist verlukast in the rat.

Verlukast, (S)3-((((3-(2-(7-chloroquinolin-2-yl)-(E)-ethenyl)phenyl)- 3-dimethylamino-3-oxopropylthio)methyl)thio)propionic acid, formerly known as MK-679, is a potent leukotriene D4 antagonist. Verlukast was incubated with rat liver microsomes under oxidative conditions to generate five metabolites, which were identified as the four possible isomeric monosulfoxides (M1-M4), and the N-hydroxymethyl amide (M5). This latter metabolite loses the elements of formaldehyde to yield the N-monomethyl amide (M6). These metabolites were isolated from a large microsomal incubation and were characterized by UV, 1H-NMR, and fast atom bombardment-MS. These data were identical to those obtained from synthetically prepared standards. Microsomal incubations of verlukast supplemented with UDP-glucuronic acid yielded the acyl glucuronide metabolite (M7), which was isolated and characterized by UV, 1H-NMR, and fast atom bombardment-M5. Verlukast was regenerated from M7 upon treatment with either beta-glucuronidase or strong aqueous base (pH greater than 11). The metabolites described above were all detected in bile collected from a rat dosed with verlukast.