Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Williams, Richard V.; Manka, Jason; Rodriguez, Alice L.; Vinson, Paige N.; Niswender, Colleen M.; Weaver, C. David; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.

doi:10.1016/j.bmcl.2011.01.044

Cited by 37 publications

(34 citation statements)

References 20 publications

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“…We chose to examine two scaffolds within the biaryl acetylene class based on the identity of the eastern aryl ring with the presence of either a phenyl or nicotinamide-based structure. In initial experiments, we used an established cell line that expresses a high density of mGlu 5 (2.3 Ϯ 0.4 pmol/mg) and has been used for discovery and extensive characterization of mGlu 5 PAMs in our previous studies (Rodriguez et al, , 2010Chen et al, 2007;Williams et al, 2011). This cell line was used to support an extensive chemical optimization and pharmacological characterization effort in which we identified VU0360172 and VU0092273 as mGlu 5 PAMs that exhibit robust ago-PAM activity.…”

Section: Resultsmentioning

confidence: 99%

“…We recently identified a novel series of mGlu 5 PAMs that are derived from a biaryl acetylene scaffold (Rodriguez et al, 2010;Williams et al, 2011) (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Dihydroxyphenylglycine (DHPG) was obtained from Ascent Scientific (Bristol, UK). ethynyl)nicotinamide (VU0360172), (6-((3-fluorophenyl)ethynyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone (VU0361747), (4-hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) (Rodriguez et al, 2010), 6-(2-phenylethynyl)-1,2,3,4-tetrahydroisoquinolin-1-one (VU0240382) (Williams et al, 2011), and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) were synthesized in-house. Unless otherwise stated, all other reagents were purchased from Sigma-Aldrich (St. Louis, MO) and were of analytical grade.…”

Section: Methodsmentioning

confidence: 99%

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Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

Noetzel

Rook²,

Vinson³

et al. 2011

Mol Pharmacol

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111

147

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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu 5 ) have emerged as an exciting new approach for the treatment of schizophrenia and other central nervous system (CNS) disorders. Of interest, some mGlu 5 PAMs act as pure PAMs, only potentiating mGlu 5 responses to glutamate whereas others [allosteric agonists coupled with PAM activity (ago-PAMs)] potentiate responses to glutamate and have intrinsic allosteric agonist activity in mGlu 5 -expressing cell lines. All mGlu 5 PAMs previously shown to have efficacy in animal models act as ago-PAMs in cell lines, raising the possibility that allosteric agonist activity is critical for in vivo efficacy. We have now optimized novel mGlu 5 pure PAMs that are devoid of detectable agonist activity and structurally related mGlu 5 ago-PAMs that activate mGlu 5 alone in cell lines. Studies of mGlu 5 PAMs in cell lines revealed that ago-PAM activity is dependent on levels of mGlu 5 receptor expression in human embryonic kidney 293 cells, whereas PAM potency is relatively unaffected by levels of receptor expression. Furthermore, ago-PAMs have no agonist activity in the native systems tested, including cortical astrocytes and subthalamic nucleus neurons and in measures of long-term depression at the hippocampal Schaffer collateral-CA1 synapse. Finally, studies with pure PAMs and ago-PAMs chemically optimized to provide comparable CNS exposure revealed that both classes of mGlu 5 PAMs have similar efficacy in a rodent model predictive of antipsychotic activity. These data suggest that the level of receptor expression influences the ability of mGlu 5 PAMs to act as allosteric agonists in vitro and that ago-PAM activity observed in cell-based assays may not be important for in vivo efficacy.

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Section: Resultsmentioning

confidence: 99%

“…We recently identified a novel series of mGlu 5 PAMs that are derived from a biaryl acetylene scaffold (Rodriguez et al, 2010;Williams et al, 2011) (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

Noetzel

Rook²,

Vinson³

et al. 2011

Mol Pharmacol

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111

147

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“…(N-clyclobutyl-6-[2-3(fluorophenyl)ethynyl]pyridine-3-carboxamine), a selective mGlu5 receptor PAM, was obtained from Vanderbilt University Medical Center (Williams et al, 2011). ETX was administered orally through the drinking water.…”

Section: Drugs and Experimental Protocolmentioning

confidence: 99%

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

D'Amore

Raaijmakers

Santolini

et al. 2016

Pharmacology Biochemistry and Behavior

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Ethosuximide (ETX) has become the drug of choice in the treatment of patients with absence seizures taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects treated with ETX failed in therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, acutely and chronically administered decreased seizures dose dependently in rats of the WAG/Rij strain, a genetic absence model. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172 as an anti-absence drug, and cognition is affected during and after chronic ETX treatment.Method: Male WAG/Rij rats were chronically treated with ETX for 4 months. EEG's were recorded during and after treatment as well as challenged with VU0360172. Rats were also periodically exposed to a cue discrimination learning task in a Y-maze. mGlu5 receptors were quantified with Western Blot.Results: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action. However, chronic ETX treated rats showed a decrease in absences both during and after the end treatment, without clear time and dose related effects. The decrease of sensitivity for VU0360172 was not accompanied by a change in mGluR5 expression in cortex and thalamus. Chronic ETX enhanced motivation to collect sucrose pallets and this was followed by an increase in cued discrimination learning.It is concluded that VU0360172 keeps its antiabsence effects after chronic treatment. Moreover, its differential effects in the two groups cannot be explained by a simple receptor down regulation suggesting a more downstream interaction between ETX and mGluR5. The cognitive enhancing effects of ETX, as found at the end of the experiment might be mediated to the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.

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“…84,85 These PAMs contained a basic acetylene core with either a benzamide or nicotinamide or related isoquinolinone and naphthridinone bicyclic ring systems. Several PAMs 47À49 were disclosed as being active in reversal of amphetamine induced hyperlocomotion (Figure 7).…”

Section: Acetylenesmentioning

confidence: 99%

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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ABSTRACT:This Review describes recent trends in the development of small molecule mGlu 5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu 5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu 5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. KEYWORDS:Metabotropic, mGlu 5 , schizophrenia, allosteric, positive allosteric modulator, DFB, CPPHA, CDPPB, ADX-47273, glutamate G lutamate is the single most important excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 The concentration of glutamate within the cytoplasm of glutamatergic neurons is several times more than that of any other amino acid, approximately 5À10 mM, and within synaptic vesicles glutamate reserves can be significantly higher. The two major receptor classes that are known to be modulated by glutamate include ionotropic glutamate receptors (iGlus), which are multimeric glutamate-gated cation channels, and metabotropic glutamate receptors (mGlus), which are seven transmembrane heptahelical (7TM) spanning proteins coupled to effector G-proteins. 2 Ionotropic glutamate receptors are responsible for fast acting glutaminergic transmission in the CNS and are mediated by the three subclasses of iGlus: the R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. All three iGlu channels undergo a conformational change and open in response to glutamate binding and induce excitatory post synaptic current, with the NMDA receptor perhaps best characterized and central to many hypotheses of CNS pathologies. A wide range of neurological disorders including chronic pain, schizophrenia, Alzheimer's disease, epilepsy, drug addiction, and fragile X syndrome have been associated with dysfunction of glutamatergic systems. 1,3 In contrast to ionotropic glutamate receptors, metabotropic glutamate receptors bind glutamate to modulate either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission.Allosteric modulation of metabotropic glutamate receptors as a glutamate-based approach for therapeutic intervention, either via enhancing or inhibiting endogenous agonist responses, is a highly active area of research and drug development. 3À7 Allosteric mechanisms of receptor modulation provide several potential advantages o...

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Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Cited by 37 publications

References 20 publications

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

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Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Cited by 37 publications

References 20 publications

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

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Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)