Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Abstract

ABSTRACT:This Review describes recent trends in the development of small molecule mGlu 5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu 5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu 5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. KEYWORDS:Metabotropic, mGlu 5 , schizophrenia, allosteric, positive allosteric modulator, DFB, CPPHA, CDPPB, ADX-47273, glutamate G lutamate is the single most important excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 The concentration of glutamate within the cytoplasm of glutamatergic neurons is several times more than that of any other amino acid, approximately 5À10 mM, and within synaptic vesicles glutamate reserves can be significantly higher. The two major receptor classes that are known to be modulated by glutamate include ionotropic glutamate receptors (iGlus), which are multimeric glutamate-gated cation channels, and metabotropic glutamate receptors (mGlus), which are seven transmembrane heptahelical (7TM) spanning proteins coupled to effector G-proteins. 2 Ionotropic glutamate receptors are responsible for fast acting glutaminergic transmission in the CNS and are mediated by the three subclasses of iGlus: the R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. All three iGlu channels undergo a conformational change and open in response to glutamate binding and induce excitatory post synaptic current, with the NMDA receptor perhaps best characterized and central to many hypotheses of CNS pathologies. A wide range of neurological disorders including chronic pain, schizophrenia, Alzheimer's disease, epilepsy, drug addiction, and fragile X syndrome have been associated with dysfunction of glutamatergic systems. 1,3 In contrast to ionotropic glutamate receptors, metabotropic glutamate receptors bind glutamate to modulate either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission.Allosteric modulation of metabotropic glutamate receptors as a glutamate-based approach for therapeutic intervention, either via enhancing or inhibiting endogenous agonist responses, is a highly active area of research and drug development. 3À7 Allosteric mechanisms of receptor modulation provide several potential advantages o...

Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

“…In light of our previous findings in which an mGluR5 agonist injected into the nucleus accumbens potentiated the interoceptive effects of a low alcohol dose (0.5 g/kg) under control conditions (Besheer et al, 2009), we hypothesized that systemically administered CDPPB would potentiate the discriminative stimulus effects of alcohol under 'normal' conditions. The CDPPB dose range tested is considered to be moderate (see Stauffer, 2011) and was selected based on pilot experiments in our lab and previously published work (Clifton et al, 2013;Fowler et al, 2011;Gass and Olive, 2009;Stefani and Moghaddam, 2010). Therefore, there is strong possibility that a higher dose range may have potentiated the interoceptive effects of alcohol, and this would need to be examined before concluding that positive allosteric modulation of mGluR5 does not potentiate the interoceptive effects of alcohol under basal conditions.…”

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

“…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).…”

“…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.…”

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

“…We searched our available mGlu 5 allosteric antagonists to identify novel compounds with weak negative cooperativity. In screening compounds within the picolinamide acetylene class series (Stauffer, 2011;Bridges et al, 2013;Turlington et al, 2013;, we noted that the mGlu 5 NAM VU0477573 (C 18 ,H 17 ,FN 2 O; molecular weight 5 296.34) showed limited negative cooperativity in inhibiting the glutamate EC 80 -induced intracellular calcium release in HEK293A cells stably expressing rat mGlu 5 (HEK293A-rat-mGlu 5 -low). The structure of VU0477573 is shown in comparison with the prototypical biaryl acetylene scaffold of the mGlu 5 NAMs MPEP and MTEP (Fig.…”