N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators

Packiarajan, Mathivanan; Ferreira, Christine G. Mazza; Hong, Sang Phyo; White, Andrew D.; Chandrasena, Gamini; Pu, Xiaosui; Brodbeck, Robbin; Robichaud, Albert J.

doi:10.1016/j.bmcl.2012.06.094

Cited by 21 publications

(8 citation statements)

References 39 publications

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“…Finally, while this review has focused on modifications to molecules that are presumed to bind to orthosteric sites of GPCRs, small structural changes have also been reported to alter the functional activity of allosteric − and biased GPCR ligands . As increasing numbers of these types of transformations are identified, it should prove interesting to compare the structure–functional activity relationships for those ligands to the cases reported in this perspective.…”

Section: Discussionmentioning

confidence: 99%

Tactical Approaches to Interconverting GPCR Agonists and Antagonists

Dosa

Amin

2015

J. Med. Chem.

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There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

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Section: Discussionmentioning

confidence: 99%

Tactical Approaches to Interconverting GPCR Agonists and Antagonists

Dosa

Amin

2015

J. Med. Chem.

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“…A growing body of evidence suggests that selective activators of the mGlu 5 subtype could provide an exciting new approach for treatment of schizophrenia and other disorders that lead to impaired cognitive function (Gregory et al, 2011;Vinson and Conn, 2012). Although discovery of selective mGlu 5 agonists that have drug-like properties has been challenging, there have been major advances in development of highly selective positive allosteric modulators (PAMs) for mGlu 5 (Liu et al, 2008;Conn et al, 2009;Stauffer, 2011;Varnes et al, 2011;Packiarajan et al, 2012). A diverse range of selective mGlu 5 PAMs have now been identified that have efficacy in animal models used to predict potential antipsychotic and cognitive enhancing activity (Gregory et al, 2011;Vinson and Conn, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Selective mGlu 5 PAMs have been developed from multiple chemical scaffolds (O'Brien et al, 2004;Kinney et al, 2005;Chen et al, 2007;Liu et al, 2008;Hammond et al, 2010;Rodriguez et al, 2010;Lamb et al, 2011;Stauffer, 2011;Varnes et al, 2011;Noetzel et al, 2012;Packiarajan et al, 2012); the majority of these mGlu 5 PAMs bind to the same site as the prototypical mGlu 5 negative allosteric modulator (NAM) MPEP (2-Methyl-6-(phenylethynyl)pyridine), located in the top third of the transmembrane spanning domains, involving transmembrane domains 3, 6, and 7 (Gregory et al, 2011). However, at least two mGlu 5 PAMs, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl] phenyl)-2-hydroxybenzamide) (O'Brien et al, 2004;Zhao et al, 2007;Chen et al, 2008) and VU0357121 (Hammond et al, 2010), have been identified that interact noncompetitively with the MPEP site.…”

Section: Introductionmentioning

confidence: 99%

A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling

et al. 2013

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Metabotropic glutamate receptor 5 (mGlu 5 ) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu 5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and longterm potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu 5 -positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu 5 , termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu 5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu 5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu 5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu 5 and potentiates mGlu 5 -mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu 5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu 5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/ LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu 5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu 5 -mediated physiologic responses in the CNS. Such stimulus bias by mGlu 5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.

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“…Amidoximes were prepared as per literature [21]. C-28 modified 1,2,4-oxadiazole esters of betulinic acid (14-25) were prepared in high yields by coupling reaction of betulinic acid (1) and 5-(bromomethyl)-3-aryl-1,2,4-oxadiazoles (2-13) in the presence of Cs 2 CO 3 at RT for overnight.…”

Section: Chemistrymentioning

confidence: 99%

“…The use of Cs 2 CO 3 in the preparation of esters from betulinic acid and alkyl halides is known [19]. The process has been applied here for the synthesis of betulinic acid-oxadiazole esters (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The synthesized compounds were screened for their in vitro cytotoxicity against three human cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Design, semisynthesis and cytotoxic activity of novel ester derivatives of betulinic acid-1,2,4 oxadiazoles

Challa

Bhargavi

Krupadanam

2016

Journal of Asian Natural Products Research

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Taking into consideration of the biological activity of betulinic acid derivatives containing a oxadiazole ring, the semisynthetic betulinic acid-1,2,4-oxadiazole esters (14-25) were synthesized starting from betulinic acid (1) and 5-(bromomethyl)-3-aryl-1,2,4-oxadiazoles (2-13) and final compounds were tested for cytotoxic activity on three human cancer cell lines in vitro. All tested compounds showed good cytotoxic activity. The structures of synthesized compounds are established based on infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry.

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N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators

Cited by 21 publications

References 39 publications

Tactical Approaches to Interconverting GPCR Agonists and Antagonists

Tactical Approaches to Interconverting GPCR Agonists and Antagonists

A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling

Design, semisynthesis and cytotoxic activity of novel ester derivatives of betulinic acid-1,2,4 oxadiazoles

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