Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand

All marketed antipsychotics act by blocking dopamine D 2 receptors. Fast dissociation from D 2 receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D 2 receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D 2 ligand. Its D 2 receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [␣ 1 , ␣ 2 , H 1 , muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D 2 antagonism (D 1 , D 3 , and 5-HT 2A ). JNJ-37822681 occupied D 2 receptors in rat brain at relatively low doses (ED 50 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED 50 (0.17 mg/kg, peripheral D 2 receptors) close to the ED 50 required for apomorphine antagonism (0.19 mg/kg, central D 2 receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D 2 antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D 2 antagonism for the treatment of schizophrenia and bipolar disorder.

The ␣ 7 nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and attention-deficit/hyperactivity disorder. Activation of ␣ 7 nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective is obtained mainly by affecting the receptor desensitization characteristics, leaving activation and deactivation kinetics as well as recovery from desensitization relatively unchanged. Choline efficacy is increased over its full concentration response range, and choline potency is increased more than 10-fold. The potentiating effect is ␣ 7 channel-dependent, because it is blocked by the ␣ 7 antagonist methyllycaconitine. Moreover, in hippocampal slices, JNJ-1930942 enhances neurotransmission at hippocampal dentate gyrus synapses and facilitates the induction of long-term potentiation of electrically evoked synaptic responses in the dentate gyrus. In vivo, JNJ-1930942 reverses a genetically based auditory gating deficit in DBA/2 mice. JNJ-1930942 will be a useful tool to study the therapeutic potential of ␣ 7 nAChR potentiation in central nervous system disorders in which a deficit in ␣ 7 nAChR neurotransmission is hypothesized to be involved.

BACKGROUND AND PURPOSEThe activation of the metabotropic glutamate receptor 2 (mGlu2) reduces glutamatergic transmission in brain regions where excess excitatory signalling is implicated in disorders such as anxiety and schizophrenia. Positive allosteric modulators (PAMs) can provide a fine-tuned potentiation of these receptors' function and are being investigated as a novel therapeutic approach. An extensive set of mutant human mGlu2 receptors were used to investigate the molecular determinants that are important for positive allosteric modulation at this receptor. EXPERIMENTAL APPROACHSite-directed mutagenesis, binding and functional assays were employed to identify amino acids important for the activity of nine PAMs. The data from the radioligand binding and mutagenesis studies were used with computational docking to predict a binding mode at an mGlu2 receptor model based on the recent structure of the mGlu1 receptor. KEY RESULTSNew amino acids in TM3 (R635, L639, F643), TM5 (L732) and TM6 (W773, F776) were identified for the first time as playing an important role in the activity of mGlu2 PAMs. CONCLUSIONS AND IMPLICATIONSThis extensive study furthers our understanding of positive allosteric modulation of the mGlu2 receptor and can contribute to improved future design of mGlu2 PAMs. Abbreviations

Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous "trigger switch" and "transmission switch" amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator. The proposed "trigger switch" for the mGlu involves the side chains of F643, N735, and W773, whereas the "transmission switch" involves the Y647, L738, and T769 amino acids. The work has wide impact on understanding mGlu GPCR function and for future allosteric modulator drugs.