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Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology.

Hammond AS, Rodriguez AL, Townsend SD, Niswender CM, Gregory KJ, Lindsley CW, Conn PJ - ACS Chem Neurosci (2010)

Bottom Line: We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site.An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396).Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.

View Article: PubMed Central - PubMed

ABSTRACT
We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure-activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu(5) limited the utility of CPPHA to explore allosteric activation of mGlu(5) at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu(5) PAM benzamide scaffold, exemplified by VU0001850 (EC(50) = 1.3 μM, 106% Glu(max)) and VU0040237 (EC(50) = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.

No MeSH data available.


Related in: MedlinePlus

Structure of MPEP-site allosteric ligand chemotypes that display modes of pharmacology switches with slight structural modifications.
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fig11: Structure of MPEP-site allosteric ligand chemotypes that display modes of pharmacology switches with slight structural modifications.

Mentions: Studies with previous series of mGlu5 allosteric modulators reveal that slight structural changes within a series can lead to striking changes in the modes of mGlu5 pharmacology of these compounds (PAM to NAM and NAM to PAM) (Figure 11). In fact, close analogues of the first mGlu5 PAM described, DFB, displayed a wide-range of modes of pharmacology with only slight structural changes (10). Replacement of the 3,3′-diF with a 3,3′-diOMe, DOMEB 14, provided an equipotent mGlu5 NAM, while the 3,3′-diCl congener, DCB 15, was the first neutral mGlu5 ligand. Subsequently, a series of mGlu5 partial antagonists 16 and 17 have also led to neutral ligands such as 5-MPEP 18(23). More recently, another mGlu5 partial antagonist 5-PEP 20 was converted into a potent, full NAM by the addition of a methyl group in the 3-position 19; in contrast, addition of either a 4-methyl group 21 or an aminomethyl moiety 22 afforded potent mGlu5 PAMs (Figure 11). Similar switches in the mode of mGlu5 pharmacology have been noted in multiple mGlu5 NAM series and in the ADX mGlu5 PAM series (15,24,25). Notably, this has only been observed in MPEP site allosteric ligands and never observed in the non-MPEP site CPPHA series. To avoid potential metabolites in vivo that might possess switches in the mode of pharmacology, it is imperative to establish whether subtle structural changes in compounds in this series of non-MPEP site ligands have a similar propensity to display fundamentally different modes of pharmacology.


Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology.

Hammond AS, Rodriguez AL, Townsend SD, Niswender CM, Gregory KJ, Lindsley CW, Conn PJ - ACS Chem Neurosci (2010)

Structure of MPEP-site allosteric ligand chemotypes that display modes of pharmacology switches with slight structural modifications.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957851&req=5

fig11: Structure of MPEP-site allosteric ligand chemotypes that display modes of pharmacology switches with slight structural modifications.
Mentions: Studies with previous series of mGlu5 allosteric modulators reveal that slight structural changes within a series can lead to striking changes in the modes of mGlu5 pharmacology of these compounds (PAM to NAM and NAM to PAM) (Figure 11). In fact, close analogues of the first mGlu5 PAM described, DFB, displayed a wide-range of modes of pharmacology with only slight structural changes (10). Replacement of the 3,3′-diF with a 3,3′-diOMe, DOMEB 14, provided an equipotent mGlu5 NAM, while the 3,3′-diCl congener, DCB 15, was the first neutral mGlu5 ligand. Subsequently, a series of mGlu5 partial antagonists 16 and 17 have also led to neutral ligands such as 5-MPEP 18(23). More recently, another mGlu5 partial antagonist 5-PEP 20 was converted into a potent, full NAM by the addition of a methyl group in the 3-position 19; in contrast, addition of either a 4-methyl group 21 or an aminomethyl moiety 22 afforded potent mGlu5 PAMs (Figure 11). Similar switches in the mode of mGlu5 pharmacology have been noted in multiple mGlu5 NAM series and in the ADX mGlu5 PAM series (15,24,25). Notably, this has only been observed in MPEP site allosteric ligands and never observed in the non-MPEP site CPPHA series. To avoid potential metabolites in vivo that might possess switches in the mode of pharmacology, it is imperative to establish whether subtle structural changes in compounds in this series of non-MPEP site ligands have a similar propensity to display fundamentally different modes of pharmacology.

Bottom Line: We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site.An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396).Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.

View Article: PubMed Central - PubMed

ABSTRACT
We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure-activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu(5) limited the utility of CPPHA to explore allosteric activation of mGlu(5) at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu(5) PAM benzamide scaffold, exemplified by VU0001850 (EC(50) = 1.3 μM, 106% Glu(max)) and VU0040237 (EC(50) = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.

No MeSH data available.


Related in: MedlinePlus