Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222.

Background And Purpose: Allosteric modulation of the mGlu2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [(3) H]-JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode.

Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782.

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 [(3)H]JNJ-40068782. In guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, JNJ-40068782 produced a leftward and upward shift in the glutamate concentration-effect curve at human recombinant mGlu2 receptors.

Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor.

Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies.

Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism.

In previous articles we have described the discovery of a new series of tricyclic isoxazolines combining central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor antagonistic activity. We report now on the synthesis, the in vitro binding potency and the primary in vivo activity of six enantiomers within this series, one of which was selected for further pharmacological evaluation and assigned as R226161. Some additional in vivo studies in rats are described with this compound, which proved to be centrally and orally active as a combined 5-HT reuptake inhibitor and alpha(2)-adrenoceptor antagonist.

Synthesis and receptor binding evaluation of clavizepine analogues with no ring D substituents.

Assembly of the azepine ring of xantheno[9,1-cd]azepines by electrophilic cyclization of sulfonamide acetals provides access to clavizepine analogues in the form of 2,12b-dihydro- or 4-hydroxy-2,3,4,12b-tetrahydro-1H-xantheno[9,1-cd]azepines, in the latter case producing the trans derivative stereoselectively. Binding assays for clavizepine and analogues at adrenergic, dopaminergic, and serotonergic receptors are reported.

Synthesis of 7-amino-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazole derivatives displaying combined alpha2-adrenoceptor antagonistic and 5-HT reuptake inhibiting activities.

Following a program searching for dual 5-HT reuptake inhibitors and alpha(2)-adrenoceptor antagonists started at Johnson & Johnson Pharmaceutical Research & Development, we now report on the synthesis of a series of 7-amino-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazole derivatives, some of which proved to be the most potent alpha(2)-adrenoceptor blockers within this chemical class of tricyclic isoxazolines, while keeping potent 5-HT reuptake inhibiting activity.

Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking activity.

The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration.

Synthesis of 3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and alpha2-adrenoceptor antagonistic activities. Part 2: Further exploration on the cinnamyl moiety.

In our previous paper we have described the synthesis of a series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, as novel dual 5-HT reuptake inhibitors and alpha2-adrenoceptor antagonists. That investigation led to the identification of the cinnamyl fragment as the most suitable moiety for combined activity. This paper outlines a further optimisation programme, focused on the exploration of the aromatic ring present on the cinnamyl moiety of compounds 1, 2 and 3.

Synthesis of 3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and alpha(2)-adrenoceptor antagonistic activities: a novel series of potential antidepressants.

The synthesis of a series of novel 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles as novel dual 5-HT reuptake inhibitors and alpha(2)-adrenoceptor antagonists is described. Their affinity at the three different human alpha(2)-adrenoceptor subtypes and the 5-HT transporter site is reported. The in vivo activity of the compounds was measured in two different assays: (1).

Synthesis and biological activities of conformationally restricted cyclopentenyl-glutamate analogues.

An efficient method for preparing conformationally restricted cyclopentenyl-glutamate analogues in a regioselective and diastereoselective manner has been developed using a formal [3 + 2] cycloaddition reaction of dehydroamino acids. Methods for preparing optically active versions of these compounds have also been devised. Of these compounds, (S)-2 is an agonist at the mGlu5 (EC(50) 18 microM) and mGlu2 (EC(50) 45 microM) receptors.