Positive and Negative Modulation of Group I Metabotropic Glutamate Receptors

Abstract

A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor's transmembrane domain was visualized.

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

“…While DPFE and VU0364289 have similar affinity for mGlu 5 , DPFE displays ∼2-fold higher cooperativity, which is greater than several reported PAM scaffolds (Kinney et al, 2005;Chen et al, 2008;Liu et al, 2008b;Vanejevs et al, 2008;Hammond et al, 2010;Rodriguez et al, 2010;Gregory et al, 2012;Gilmour et al, 2013). In agreement with our recent findings, potentiation by these N-aryl piperazine PAMs was attributable to a mechanism solely involving glutamate efficacy modulation.…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…In fact, compound V shown in Table 5 (Sharma et al, 2009) is one of the most potent mGlu5 receptor positive allosteric modulators known to date (EC 50 ϭ 14 nM), and it is based on an MPEP-like scaffold! Positive mGlu5 receptor modulators based on the MPEP-scaffold have also been described by other groups (Vanejevs et al, 2008;Ritzén et al, 2009) and, most recently, Rodriguez et al (2010) (compound VIII in Table 5). The first positive mGlu5 receptor modulators, however, were reported by O'Brien et al (2003).…”

“…Subsequently, several novel negative allosteric mGlu1 receptor modulators (Table 6) were described that in functional in vitro assays had high potencies with IC 50 values in the low nanomolar range: (3,4- (Lavreysen et al, 2004), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo [3,2-a]benzimidazole-2-carboxamide hydrochloride (YM-298198) (Kohara et al, 2005) (Kohara et al, 2007), FTIDC (Suzuki et al, 2007a), 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (Fukuda et al, 2009) and compounds IX (Micheli et al, 2003) and X (Zheng et al, 2005) in Table 6. A number of additional negative allosteric mGlu1 receptor modulators (not shown in Table 6) have been described; their structures are given in the respective references (Mabire et al, 2005;Micheli et al, 2006;Di Fabio et al, 2007;Owen et al, 2007;Vanejevs et al, 2008;Sasikumar et al, 2009;Satoh et al, 2009). Some of these molecules showed good in vivo-activity, especially in models for chronic pain (see below).…”

Investigating Metabotropic Glutamate Receptor 5 Allosteric Modulator Cooperativity, Affinity, and Agonism: Enriching Structure-Function Studies and Structure-Activity Relationships

“…1C). In contrast, the potencies of mGlu 5 PAMs were often higher than their estimated affinities at the prototypical allosteric site labeled with Poon et al, 2004;Roppe et al, 2004;Chua et al, 2005;Tehrani et al, 2005;de Paulis et al, 2006;Kulkarni et al, 2006Kulkarni et al, , 2009Jaeschke et al, 2007;Milbank et al, 2007;Liu et al, 2008;Vanejevs et al, 2008;Felts et al, 2009Felts et al, , 2010Galambos et al, 2010;Rodriguez et al, 2010;Wágner et al, 2010;Zhang et al, 2010;Alagille et al, 2011;Gilbert et al, 2011;Lindemann et al, 2011;Sams et al, 2011;Weiss et al, 2011;Zou et al, 2011;Mueller et al, 2012). Dashed lines, unity; dotted lines, potency and affinity within 3-fold of each other; solid lines, 10-fold difference.…”