Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC 50 values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of Ͼ50-fold the in vitro EC 50 value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of L-DOPA (6 mg/kg) enabled a robust, dosedependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of L-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of L-DOPA was not associated with an exacerbation of L-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinson's disease.

There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu 4 ) leads to anxiolytic-and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu 4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolyticlike efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu 4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressantlike efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu 4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.

The Cu-catalyzed intramolecular CH insertion of phenyliodonium ylide 1b was investigated at 08 in the presence of several chiral ligands. Enantioselectivities varied in the range 38 ± 72%, and were higher than those resulting from reaction of the diazo compound 1c at 658. The intramolecular insertion of the enantiomerically pure methyl diazoacetate (R)-20 and of the corresponding phenyliodonium ylide (R)-21 proceeded to (R)-23 with retention of configuration with [Cu(hfa) 2 ] (hfa hexafluoroacetylacetone 1,1,1,5,5,5-hexafluoropentane-2,4-dione) and [Rh 2 (OAc) 4 ]. These results are consistent with a carbenoid mechanism for the Cu-catalyzed insertion with phenyliodonium ylides. However, the insertion of the perfluorosulfonated phenyliodonium ylide (R)-29 afforded with [Cu(hfa) 2 ] as well as with [Rh 2 (OAc) 4 ] the cyclopentanone derivative 30 as a cis/trans mixture with only 56 ± 67% enantiomeric excess.Introduction. ± The decomposition of diazo compounds in the presence of transition metals leads to reactions typical for metal-carbenoid intermediates, such as cyclopropanations, insertions into XÀH bonds, and formation of ylides with heteroatoms having lone pairs available. The Cu-catalyzed asymmetric cyclopropanation is probably the most popular application of the transition-metal-catalyzed carbenoid reactions [1]. In addition, Cu-catalyzed decomposition of diazo compounds may also lead to CH bond insertions, although Rh II catalysts are usually more appropriate for these latter transformations [2]. The Rh II -catalyzed insertion proceeds with retention of configuration at the C-atom undergoing the reaction [3], and all the experimental evidence is consistent with a mechanism involving a rhodium-carbenoid as the reactive intermediate [4]. In contrast, the mechanism of the Cu-catalyzed CH insertion has not been investigated systematically, but is assumed to be analogous to that of the reactions catalyzed by Rh II .Since diazo compounds are potentially explosive, toxic, and cancerogenic [5], the number of their industrial applications is limited [6]. Phenyliodonium ylides are potential substitutes for diazo compounds in metal-carbenoid reactions. Their photochemical [7] [8], thermal [8] [9], and transition-metal-catalyzed [10] decompositions exhibit analogies to that of diazo compounds, and, accordingly, carbene or carbenoid intermediates are usually assumed to be involved in these reactions [9 ± 11] although little effort has been made to demonstrate the involvement of these putative species. Some years ago, we presented evidence for metal-carbenoid pathways in Rh II -catalyzed cyclopropanation and CH insertion reactions [11].The mechanism of the Cu I -catalyzed decomposition of phenyliodonium ylides is controversial. Originally, Hayasi et al. proposed a copper-complexed carbene intermediate in the Cu I -catalyzed decomposition of phenyliodonium ylides derived

Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.

A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.