Dipyridyl amides: potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists

The mGlu5 receptor has been implicated in a number of CNS disorders. Herein, we report on the discovery, synthesis, and biological evaluation of dipyridyl amides as small molecules mGluR5 antagonists.     

Cyclohexenyl- and dehydropiperidinyl-alkynyl pyridines as potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists

Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.     

Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists

A series of diaryl amides was designed and synthesized as novel nonethynyl mGluR5 antagonists. The systematic variation of the pharmacophoric groups led to the identification of a lead compound that demonstrated micromolar affinity for the mGluR5. Further optimization resulted in compounds with improved binding affinities and antagonist profiles, in vitro.     

Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists

Investigation of a series of heterobicyclic compounds with essential pharmacophoric features of the metabotropic glutamate receptor 5 (mGluR5) antagonists MPEP and MTEP provided novel structural templates with sub-micromolar affinities at the mGluR5.     

Rational design of 7-arylquinolines as non-competitive metabotropic glutamate receptor subtype 5 antagonists

Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.     

Design and synthesis of novel heterobiaryl amides as metabotropic glutamate receptor subtype 5 antagonists

A series of heterobiaryl amides was designed and synthesized as novel mGluR5 antagonists. The synthesis using palladium catalyzed Suzuki-Miyaura cross-coupling reactions provided an array of compounds with a range of in vitro activities. In particular, compound 9e, 4(3,5-difluorophenyl)-N-(6-methylpyridin-1-yl)picolinamide, exhibited nanomolar affinity at the mGluR5 and will serve as a template for future drug design.     

Piperidinyl-nicotinamides as potent and selective somatostatin receptor subtype 5 antagonists

Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2′ have been discovered as potent and selective SST5 antagonists. The activity (K_i) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer.     

(3)H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5

The synthesis of a new potent, subtype-selective radioligand [(3)H]-M-MPEP (2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine) and its in vitro pharmacological characteristics are described. Science Ltd.     

Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists

SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT_2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo.     

3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists

Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.     

Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor

We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency and the brain to plasma ratio of the initial lead led to the discovery of 5 and 23 (EC50=111 and 5 nM, respectively).     

Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity

Structure-activity relationship studies focused on bio-isosteric replacements of 2-pyridyl resulted in mGlu5 receptor antagonists with reduced inhibition of cytochrome P450 1A2. This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity.     

Isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists

This Letter describes the synthesis and evaluation of mGluR7 antagonists in the isoxazolopyridone series. In the course of modification in this class, novel solid support synthesis of the isoxazolopyridone scaffold was developed. Subsequent chemical modification led to the identification of several potent derivatives with improved physicochemical properties compared to a hit compound 1. Among these, 2 showed good oral bioavailability and brain penetrability, suggesting that 2 may be useful for in vivo study to elucidate the role of mGluR7.     

Negative cooperativity of glutamate binding in the dimeric metabotropic glutamate receptor subtype 1

Metabotropic glutamate receptor (mGluR) subtype 1 is a Class III G-protein-coupled receptor that is mainly expressed on the post-synaptic membrane of neuronal cells. The receptor has a large N-terminal extracellular ligand binding domain that forms a homodimer, however, the intersubunit communication of ligand binding in the dimer remains unknown. Here, using the intrinsic tryptophan fluorescence change as a probe for ligand binding events, we examined whether allosteric properties exist in the dimeric ligand binding domain of the receptor. The indole ring of the tryptophan 110, which resides on the upper surface of the ligand binding pocket, sensed the ligand binding events. From saturation binding curves, we have determined the apparent dissociation constants (K(0.5)) of representative agonists and antagonists for this receptor (3.8, 0.46, 40, and 0.89 microm for glutamate, quisqualate, (S)-alpha-methyl-4-carboxyphenylglycine ((S)-MCPG), and (+)-2-methyl-4-carboxyphenylglycine (LY367385), respectively). Calcium ions functioned as a positive modulator for agonist but not for antagonist binding (K(0.5) values were 1.3, 0.21, 59, and 1.2 microm for glutamate, quisqualate, (S)-MCPG, and LY367385, respectively, in the presence of 2.0 mm calcium ion). Moreover, a Hill analysis of the saturation binding curves revealed the strong negative cooperativity of glutamate binding between each subunit in the dimeric ligand binding domain. As far as we know, this is the first direct evidence that the dimeric ligand binding domain of mGluR exhibits intersubunit cooperativity of ligand binding.     

3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor

The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.     

Allosteric activation of metabotropic glutamate receptor 5

Abstract

Metabotropic glutamate receptor 5 (mGluR5) is a class C G protein-coupled receptor (GPCR) with both an extracellular ligand binding site and an allosteric intrahelical chamber located similarly to the orthosteric ligand binding site of Class A GPCRs. Ligands binding to this ancestral site of mGluR5 can act as positive (PAM), negative (NAM) or silent (SAM) allosteric modulators, and their medicinal chemistry optimization is notoriously difficult, as subtle structural changes may cause significant variation in activity and switch in the functional response. Here we present all atom molecular dynamics simulations of NAM, SAM and PAM complexes formed by closely related ligands and analyse the structural differences of the complexes. Several residues involved in the activation are identified and the formation of a continuous water channel in the active complex but not in the inactive ones is recognized. Our results suggest that the mechanism of mGluR5 activation is similar to that of class A GPCRs.

Communicated by Ramaswamy H. Sarma     

Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu₅ NAM clinical candidate that failed in non-human primate (NHP) 28?day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp³ character, uniform CYP₄₅₀-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.     

Blockade of amygdala metabotropic glutamate receptor subtype 1 impairs fear extinction

The metabotropic glutamate receptor subtype 1 (mGluR1) is thought to be crucial for several forms of memory, but its role in memory extinction has not been determined. Here, we examined a role of mGluR1 in the extinction of conditioned fear using microinjection of an mGluR1 antagonist, CPCCOEt, into the lateral amygdala (LA), a critical structure for fear conditioning and extinction. Intra-LA injection of 3 microg CPCCOEt impaired extinction that was initiated 48 h after the conditioning, but not that initiated 2h after the conditioning, indicating that the effectiveness of CPCCOEt depends upon the length of time since fear conditioning. The CPCCOEt injection failed to alter an mGluR1-like receptor (mGluR5)-dependent acquisition of fear memory, further supporting the specificity of the injected CPCCOEt on mGluR1. Together, our results suggest that amygdala mGluR1 plays a critical role in the extinction of learned fear, but not in the acquisition of fear memory.     

Supraspinal metabotropic glutamate receptor subtype 8: a switch to turn off pain

Glutamate is the main excitatory neurotransmitter in the central nervous system and as such controls the majority of synapses. Glutamatergic neurotransmission is mediated via ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). Signaling via mGluRs permits to finely tune, rather than turning on/off, the excitatory neurotransmission as the iGluRs do. Eight mGluRs (mGluR1-8) have been cloned so far, which have been divided into three groups based on sequence homology, pharmacological properties and second messenger signaling. mGluRs are widely expressed both on glia and neurons. On neurons they are located both at postsynaptic (group I) and presynaptic sites (group II and III). Group II and III mGluR stimulation reduces glutamate release, which can prove useful in pathological conditions characterized by elevated glutamatergic neurotransmission which include chronic pain. Indeed, mGluRs are widely distributed on pain neuraxis. The recent development of selective mGluR ligands has permitted investigating the individual role of each mGluR on pain control. The development of (S)-3,4-dicarboxyphenylglycine, a selective mGluR8 agonist, has revealed the mGluR8 role in inhibiting pain and its related affective consequences in chronic pain conditions. mGluR8 proved also to be overexpressed in pain controlling areas during pathological pain guaranteeing the availability of a switch for turning off abnormal pain. Thus, mGluR8 corresponds to an ideal target in designing novel analgesics. This review will focus on the novel insights into the mGluR8 role on pain control, with particular emphasis on the supraspinal descending pathway, an antinociceptive endogenous source, whose activation or disinhibition (via mGluR8) induces analgesia.     

A new series of pyridinyl-alkynes as antagonists of the metabotropic glutamate receptor 5 (mGluR5)

Synthesis and some structure-activity relationships for a new series of propargyl ethers as mGluR5 antagonists are reported.