In vitro evaluation of a large chemical library of pharmacologically acceptable prototpe compounds in a

R214127 was shown to be a potent and noncompetitive metabotropic glutamate 1 (mGlu1) receptor-selective antagonist. The kinetics and pharmacology of [ H]R214127 binding in rat brain was investigated in more detail by radioligand autoradiography. A high density of binding sites was detected in the molecular layer of the cerebellum. Moderate labeling was seen in the CA3 and dentate gyrus of the hippocampus, thalamus, olfactory tubercle, amygdala, and substantia nigra reticulata. The cerebral cortex, caudate putamen, ventral pallidum, and nucleus accumbens showed lower labeling. The high affinity and selectivity of [ 3 H]R214127 for mGlu1 receptors renders this compound the ligand of choice to study the native mGlu1 receptor in brain.Eight metabotropic glutamate (mGlu) receptors have been cloned to date. These G protein-coupled glutamate receptors have been divided into three groups based on sequence homology, second-messenger coupling, and pharmacology . Numerous studies have been performed to elucidate the role of these receptors in physiological and pathological conditions of the central nervous system. Group I mGlu receptors, which comprise the mGlu1 and mGlu5 receptors and several splice variants thereof, in particular have received quite some attention. Several studies have provided clues that group I receptors play a physiological role in regulating ion channels and synaptic transmission and in synaptic plasticity that underlies learning and memory (Pin and Duvoisin, 1995). Overactivation of these mGlu receptors ABBREVIATIONS: mGlu, metabotropic glutamate; CHO-dhfr Ϫ cells, dihydrofolate reductase-deficient Chinese hamster ovary cells; R214127, 1-(3,4-dihydro-2H-pyrano [2,3-b]quinolin-

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulatorin clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of 14 C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 ؎ 6.6%) and much less in feces (2.5 ؎ 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species. (Rogawski, 2006). In preclinical studies (data on file), this drug has demonstrated broad anticonvulsant activity in acute rodent seizure models and in the kindled rat model of partial epilepsy. It has shown efficacy in attenuating the frequency of spontaneous recurrent seizures in the kainite post-status epilepticus rat model of temporal lobe epilepsy (Grabenstatter and Dudek, 2004) and suppressing spike and wave discharges in the GAERS (Genetic Absence Epilepsy Rat from Strasbourg) model of generalized absence epilepsy (Nehlig et al., 2005). Overall, the preclinical profile suggests that the drug will be useful in the treatment of epilepsy and other neurologic conditions where neurostabilization is desirable. RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a new neuromodulator currently under clinical investigation for adjunctive treatment of epilepsyThe objective of the present study was to investigate the absorption, metabolism, and excretion of RWJ-333369 in humans and to identify and quantify its major and minor metabolites after a single oral dose of 500 mg of 14 C-RWJ-333369 to healthy male subjects. absorption, distribution, metabolism, and excretion characterization of RWJ-333369 in preclinical species and comparison ...

No undue tissue accumulation of TR and of bortezomib was observed in rats following a full clinical dosing cycle of bortezomib.