2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.

1 In order to explore potential therapeutic implications of cannabinoid antagonists, the eects of the prototypical cannabinoid antagonist SR141716A on monoamine eux from the medial prefrontal cortex and the nucleus accumbens of the rat were investigated by in vivo microdialysis. 2 SR141716A moderately increased serotonin eux and concentrations of its metabolite 5-HIAA, both in the medial prefrontal cortex and the nucleus accumbens, and increased norepinephrine, dopamine and their metabolites in the medial prefrontal cortex. In contrast, it had no eect on norepinephrine, dopamine and their metabolites in the nucleus accumbens. 3 At the same doses, SR141716A increased acetylcholine eux in the medial prefrontal cortex, in agreement with previous studies; contrary to the eects in cortex, SR141716A had no eect on acetylcholine eux in the nucleus accumbens. 4 The ecacy of SR141716A in the psychostimulant-induced hyperlocomotion and the forced swimming paradigms was also explored in mice. SR141716A attenuated phenylcyclidine-and damphetamine-induced hyperlocomotion, without aecting locomotor activity when administered alone, and decreased immobility in the forced swimming test. 5 These results suggest that the cortical selectivity in the release of catecholamines, dopamine in particular, induced by the cannabinoid antagonist SR141716A, its procholinergic properties, together with its mild stimulatory eects on serotonin and norepinephrine eux make similar compounds unique candidates for the treatment of psychosis, aective and cognitive disorders.

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These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU K5 in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU K5 -selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR), the most potent GLU K5 antagonist described to date. Comparisons were made to the competitive GLU K5 /␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU K5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 M)-induced currents with an IC 50 value of 0.045 Ϯ 0.011 M. In HEK293 cells transfected with GLU K5 , GLU K2 /GLU K5 , or GLU K5 /GLU K6 receptors, LY466195 produced IC 50 values of 0.08 Ϯ 0.02, 0.34 Ϯ 0.17, and 0.07 Ϯ 0.02 M, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID 100 value of 100 g/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 g/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 g/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.Glutamate is the major excitatory neurotransmitter in the central nervous system and can act at three major types of ligand-gated ion channels that are defined by the activity of the subtype-selective agonists N-methyl-D-aspartate (NMDA), kainate, and ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (Collingridge and Lester, 1989). Five kainate receptors subtypes have been cloned and classified as either high-affinity (GLU K1 and GLU K2 ) or lowArticle, publication date, and citation information can be found at