A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

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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-

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.