Development and profiling of mGlu7 NAMs with a range of saturable inhibition of agonist responses in vitro

Abstract

We describe here a series of metabotropic glutamate receptor 7 (mGlu₇) negative allosteric modulators (NAMs) with a saturable range of activity in inhibiting responses to an orthosteric agonist in two distinct in vitro pharmacological assays. The range of inhibition among compounds in this scaffold provides highly structurally related ligands with differential degrees of receptor blockade that can be used to understand inhibitory efficacy profiles in native tissue or in vivo.

Keywords: Metabotropic glutamate receptor; Positive Allosteric modulator (PAM); Structure Activity Relationship (SAR); mGlu(7).

Fig. 1.

Structures of orthosteric antagonist LY341495 (1), early generation mGlu₇ NAMs ADX71743 (2), and MMPIP (3), and recently reported mGlu₇ NAM tool compounds (4–6). PPB = plasma protein binding, K_p = brain:plasma ratio, K_p,uu = unbound Brain:plasma ratio.

Fig. 2.

(A) VU6010608 (4) and VU6019279 (14f in reference 15) exhibit differential cooperativity in an mGlu₇/G_α15-mediated calcium mobilization assay. (B) Inhibitoiy effect of 10 μM VU6010608 on agonist CRC in an mGlu₇ GIRK assay. No effect was seen on other mGlu receptor subtypes (data not shown) indicating an mGlu₇-specific response.

Fig. 3.

Two additional NAMs used in correlation analyses in Fig. 4.

Fig. 4.

Correlation of EC_MIN (A) and pIC₅₀ (B) values across a series of mGlu₇ NAMs in two molecular pharmacology assays. Lines were fit using linear regression.

Fig. 5.

Comparison of activity of 14a (VU6019281) in either calcium (black circles) or GIRK (white circles) assays.

Scheme 1.

Synthesis of analogs 7b and 7d.

Scheme 2.

Synthesis of analogs 14a and 14e.

Scheme 3.

Synthesis of analog 19f.

Scheme 4.

Synthesis of analog 19g.