New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): Identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones

doi:10.1016/j.bmcl.2010.12.048

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 3, 1 February 2011, Pages 971-976

https://doi.org/10.1016/j.bmcl.2010.12.048 Get rights and content

Abstract

A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.

Graphical abstract

Section snippets

Acknowledgments

The authors thank members of the purification and analysis group; and the in vitro metabolism team from the discovery ADME/Tox group.

References and notes (23)

G. Tresadern et al.
Bioorg. Med. Chem. Lett.
(2010)
H. Brauner-Osborne et al.
Curr. Drug Targets
(2007)
C.J. Swanson et al.
Nat. Rev. Drug Disc.
(2005)
R. Shigemoto et al.
J. Neurosci.
(1997)
S.T. Patil et al.
Nat. Med.
(2007)
D.R. Weinberger
Nat. Med.
(2007)
M.L. Woolley et al.
Psychopharmacology
(2008)
M.J. Fell et al.
J. Pharmacol. Exp. Ther.
(2008)
J.P. Conn et al.
Nat. Rev. Drug Disc.
(2009)

A.A. Trabanco et al.

Curr. Med. Chem.

(2011)

Cited by (20)

Selectivity and evolutionary divergence of metabotropic glutamate receptors for endogenous ligands and G proteins coupled to phospholipase C or TRP channels
2014, Journal of Biological Chemistry
Citation Excerpt :
The −log10(EC50) from mGluR2 transfected HEK/TRPC4β cells is 4.63 ± 0.12. The potency observed in these experiments is within the previously reported −log10(EC50) range of 4.69–5.39 for mGluR2 (26), although less potent than reported for responses based on G protein-regulated inwardly rectifying potassium channels (GIRK) and a thallium flux assay, where the −log10(EC50) was found to be 5.1 (27). Similar results were observed for HEK/TRPC4β cells transfected with mGluR4 or mGluR6 (Fig. 5, C and E).
To define the upstream and downstream signaling specificities of metabotropic glutamate receptors (mGluR), we have examined the ability of representative mGluR of group I, II, and III to be activated by endogenous amino acids and catalyze activation of G proteins coupled to phospholipase C (PLC), or activation of G_i/o proteins coupled to the ion channel TRPC4β. Fluorescence-based assays have allowed us to observe interactions not previously reported or clearly identified. We have found that the specificity for endogenous amino acids is remarkably stringent. Even at millimolar levels, structurally similar compounds do not elicit significant activation. As reported previously, the clear exception is l-serine-O-phosphate (l-SOP), which strongly activates group III mGluR, especially mGluR4,-6,-8 but not group I or II mGluR. Whereas l-SOP cannot activate mGluR1 or mGluR2, it acts as a weak antagonist for mGluR1 and a potent antagonist for mGluR2, suggesting that co-recognition of l-glutamate and l-SOP arose early in evolution, and was followed later by divergence of group I and group II mGluR versus group III in l-SOP responses. mGluR7 has low affinity and efficacy for activation by both l-glutamate and l-SOP. Molecular docking studies suggested that residue 74 corresponding to lysine in mGluR4 and asparagine in mGluR7 might play a key role, and, indeed, mutagenesis experiments demonstrated that mutating this residue to lysine in mGluR7 enhances the potency of l-SOP. Experiments with pertussis toxin and dominant-negative Gα_i/o proteins revealed that mGluR1 couples strongly to TRPC4β through Gα_i/o, in addition to coupling to PLC through Gα_q/11.
MGluR2 Activators and mGluR5 Blockers Advancing in the Clinic for Major CNS Disorders
2012, Annual Reports in Medicinal Chemistry
Citation Excerpt :
The triazolo[4,3:a]pyridine series (chemotype C) was exemplified in several patent applications with compounds demonstrated efficacy in different models of psychosis,39,40 illustrated by compounds 26 and 27 (EC50 = 1.6 and 16.2 nM, respectively). Phenyl-piperidine 27 exhibited efficacy in PCP-induced hyperlocomotion in mice (ED50 = 5.4 mg/kg) and conditioned avoidance response in rats (ED50 = 16.3 mg/kg, p.o.).41 The oxazolidinone derivative 28 (EC50 = 450 nM) was identified in an HTS calcium mobilization assay on hmGluR2 cell lines.
Metabotropic glutamate receptors (mGluRs) belong to the Class C G-protein coupled receptor and are activated by glutamate, a major neurotransmitter in the brain. The widespread expression of mGluR, in particular, mGluR2 and mGluR5 subtypes, throughout the central nervous system has made those two receptors attractive therapeutic targets for the treatment of severe neurological disorders, such as schizophrenia, anxiety, Parkinson's disease levodopa-induced dyskinesia, fragile X syndrome, and major depressive disorders. This review therefore focuses on the drug discovery efforts and clinical status of mGluR2 activators acting as orthosteric agonists or positive allosteric modulators as well as negative allosteric modulators of mGluR5.
Ni-catalyzed reductive and merged photocatalytic cross-coupling reactions toward Sp<sup>3</sup>/Sp<sup>2</sup>-functionalized isoquinolones: Creating diversity at C-6 and C-7 to address bioactive analogues
2020, ACS Omega
Nano-ZnO as valuable catalyst for organic transformations: A review
2020, Research Journal of Chemistry and Environment
Expeditious Synthesis of Isoquinolone Derivatives by Rhodium(I)-Catalyzed Annulation Reaction through C-C Bond Cleavage
2019, Organic Letters
Isoquinolinones (Update 2018)
2018, Science of Synthesis

View all citing articles on Scopus

View full text

New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): Identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem. Lett.

Curr. Drug Targets

Nat. Rev. Drug Disc.

J. Neurosci.

Nat. Med.

Nat. Med.

Psychopharmacology

J. Pharmacol. Exp. Ther.

Nat. Rev. Drug Disc.

Curr. Med. Chem.