Metabotropic glutamate receptor subtype 5 (mGlu5) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu5 PAMs do not activate mGlu5 directly but selectively potentiate activation of mGlu5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu5 activation and achieving optimal in vivo effects.
Using specially engineered mGlu5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate.
Both in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations.
Loss of the absolute dependence of mGlu5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia.
Glutamate; allosteric modulators; agonist; schizophrenia; seizure; convulsions; mGlu5
In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [18F]fallypride administration to estimate the distribution volume ratio DVR′ (DVR′ ∝ DVR; DVR = 1 + BPND, where BPND is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [18F]fallypride DVR′.
Rats were injected with [18F]fallypride either unconsciously under ~1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [18F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [18F]fallypride i.v. while under 1.5% isoflurane. The DVR′ estimates from the 60 min acquisitions were compared with the DVR′ from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time–activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k3/k4 (≈ BPND) for the 60 and 120 min acquisitions.
Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR′ estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ~30% reduction in k3/k4 for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer).
The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [18F]fallypride BPND in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors.
[18F]fallypride; dopamine (DA) receptors; isoflurane; graphical analysis; microPET
Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu2 and mGlu4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.
Development of SAR in an N-acyl-N′-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats.
Glutamate; GPCR; mGlu1; Allosteric modulator; CNS; Piperazine
The newly formed Academic Drug Discovery Consortium (ADDC) aims to support the growing numbers of university centres engaged in drug discovery that have emerged in response to recent changes in the drug discovery ecosystem.
A multi-dimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with sub-micromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.
Metabotropic glutamate receptor; mGlu3; negative allosteric modulator (NAM); ML337; MLPCN probe
This letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10 μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409 nM and 480 nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s <30 μM) and a robust 20-fold leftward shift of the ACh CRC.
Muscarinic acetylcholine receptors; M5; Positive allosteric modulator (PAM); ML326
Currently available therapeutic agents for treatment of schizophrenia target signaling by monoaminergic neurotransmitters; however, these treatments do not adequately treat the range of symptoms observed in patients. While these therapies treat the positive symptoms, they do not have efficacy in treating the negative symptoms and cognitive deficits that are associated with the disease. Evidence suggests that molecules that modulate signaling by the neurotransmitter acetylcholine (ACh) could provide a more comprehensive treatment of schizophrenia than currently prescribed antipsychotics. Molecules that broadly increase ACh-signaling have been demonstrated to have efficacy in treating numerous symptom clusters in schizophrenia patients. Unfortunately, these compounds induce adverse effects via activation of peripheral receptors that limit their clinical utility. One proposed strategy for retaining the efficacy of cholinergic treatments, without the adverse effects, is to target specific cholinergic receptor subtypes in the brain. Several cholinergic receptors are able to modulate brain circuits that are dysregulated in schizophrenia patients including receptors belonging to both the muscarinic family (i.e., M1, M4, and M5), and the nicotinic family (i.e., α7, α4β2). Recently, great strides have been made in developing small molecules with high specificity for these receptors, and several of these novel molecules have robust efficacy in several preclinical models predictive of both anti-psychotic and pro-cognitive effectiveness. Promising studies suggest that targeting M1 and α7 may be beneficial for pro-cognitive effects, while molecules that target M4 may be ideally suited to address the positive symptoms. Since these receptor subtypes are distinct from those responsible for the adverse effects observed with non-selective cholinergic treatments, there is hope that molecules targeting these receptors could provide novel therapeutics. Further research is needed to examine the utility of such compounds as therapeutics that could be used either alone, or in combination with existing medications, to better treat schizophrenia.
Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, β-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous Gs-coupled receptors, such as β-adrenergic receptors.
β-adrenergic; cAMP-dependent protein kinase; mGluR4; mGluR7; mGluR8; phosphorylation
Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking. Novel compounds that regulate signaling by the major excitatory neurotransmitter in the brain, glutamate, are emerging as a novel approach for the treatment of this disorder. Currently available medications ameliorate positive symptoms but do not have efficacy in reducing negative symptoms or cognitive disturbances. It is possible that agents that target glutamatergic signaling in the CNS could have efficacy in reducing all major symptom clusters, providing a more comprehensive treatment strategy, and also avoiding some of the adverse effects that are seen with currently available treatments. Three major approaches for targeting glutamate signaling are now advancing in preclinical and clinical development. First are inhibitors for a transporter for glycine termed GlyT1. Glycine is a co-agonist with glutamate for a specific subtype of glutamate receptor, termed the NMDA receptor, which is thought to be critically involved in brain circuits that are disrupted in schizophrenia patients. Inhibiting GlyT1 increases glycine levels and can selectively increase NMDA receptor signaling. Another promising approach is to increase activity of another family of glutamate receptors, termed metabotropic glutamate receptors (mGlus), which play important modulatory roles in brain circuits that are thought to be disrupted in schizophrenia patients. Activation of the group I (mGlu5) and the group II (mGlu2 and mGlu3) mGlus is hypothesized to normalize the disruption of aberrant signaling in these circuits. Novel drug-like molecules that increase activity of these receptors have robust efficacy in animal models that predict efficacy in treatment of schizophrenia. Early clinical studies provide some support for potential utility of these targets in reducing symptoms in schizophrenia patients. Clinical studies that are underway will provide further insights into the potential utility of these compounds in the treatment of multiple symptom domains in schizophrenia patients.
This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6- membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype.
Muscarinic acetylcholine receptor 1; M1; Spirocyclic; Positive allosteric modulator (PAM); ML137; VU0413162
Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu4 belongs to a subfamily of mGlus that is predominantly coupled to Gi/o G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu4-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu4 depends upon the presence of H1 histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu4-mediated signaling events downstream of Gi/o G proteins, such as cAMP inhibition, suggesting that the presence of Gq coupled receptors such as H1 may bias normal mGlu4-mediated Gi/o signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu4 is assessed, the potentiated signaling of mGlu4 is further biased by histamine toward calcium-dependent pathways. These results suggest that Gi/o-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of Gq receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when Gq receptors are co-activated.
This article is part of a Special Issue entitled ‘mGluR’
Glutamate; Histamine; Receptor; Allosteric modulator; Functional selectivity
Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson’s disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu8-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (two hour) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18–20 hours) or reserpine (18–20 hours), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 hour pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu8 may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D2-like dopamine receptors is prolonged and indicate that selective activation of mGlu8 may represent a novel therapeutic strategy for alleviating the motor symptoms of PD.
The medial prefrontal cortex (mPFC) serves executive cognitive functions such as decision-making that are impaired in neuropsychiatric disorders and pain. We showed previously that amygdala-driven abnormal inhibition and decreased output of mPFC pyramidal cells contribute to pain-related impaired decision-making (Ji et al., 2010). Therefore, modulating pyramidal output is desirable therapeutic goal. Targeting metabotropic glutamate receptor subtype mGluR5 has emerged as a cognitive-enhancing strategy in neuropsychiatric disorders, but synaptic and cellular actions of mGluR5 in the mPFC remain to be determined. The present study determined synaptic and cellular actions of mGluR5 to test the hypothesis that increasing mGluR5 function can enhance pyramidal cell output.
Whole-cell voltage- and current-clamp recordings were made from visually identified pyramidal neurons in layer V of the mPFC in rat brain slices. Both the prototypical mGluR5 agonist CHPG and a positive allosteric modulator (PAM) for mGluR5 (VU0360172) increased synaptically evoked spiking (E–S coupling) in mPFC pyramidal cells. The facilitatory effects of CHPG and VU0360172 were inhibited by an mGluR5 antagonist (MTEP). CHPG, but not VU0360172, increased neuronal excitability (frequency– current [F–I] function). VU0360172, but not CHPG, increased evoked excitatory synaptic currents (EPSCs) and amplitude, but not frequency, of miniature EPSCs, indicating a postsynaptic action. VU0360172, but not CHPG, decreased evoked inhibitory synaptic currents (IPSCs) through an action that involved cannabinoid receptor CB1, because a CB1 receptor antagonist (AM281) blocked the inhibitory effect of VU0360172 on synaptic inhibition. VU0360172 also increased and prolonged CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI). Activation of CB1 with ACEA decreased inhibitory transmission through a presynaptic mechanism.
The results show that increasing mGluR5 function enhances mPFC output. This effect can be accomplished by increasing excitability with an orthosteric agonist (CHPG) or by increasing excitatory synaptic drive and CB1-mediated presynaptic suppression of synaptic inhibition (“dis-inhibition”) with a PAM (VU0360172). Therefore, mGluR5 may be a useful target in conditions of impaired mPFC output.
mGluR5; Positive allosteric modulator; PAM; CB1; Prefrontal cortex; Synaptic transmission
Alzheimer’s disease (AD) and schizophrenia (SZ) are neurological disorders with overlapping symptomatology, including both cognitive deficits and behavioral disturbances. Current clinical treatments for both disorders have limited efficacy accompanied by dose-limiting side effects, and ultimately fail to adequately address the broad range of symptoms observed. Novel therapeutic options for AD and SZ are needed to better manage the spectrum of symptoms with reduced adverse-effect liability. Substantial evidence suggests that activation of muscarinic acetylcholine receptors (mAChRs) has the potential to treat both cognitive and psychosis-related symptoms associated with numerous central nervous system (CNS) disorders. However, use of nonselective modulators of mAChRs is hampered by dose-limiting peripheral side effects that limit their clinical utility. In order to maintain the clinical efficacy without the adverse-effect liability, efforts have been focused on the discovery of compounds that selectively modulate the centrally located M1 and M4 mAChR subtypes. Previous drug discovery attempts have been thwarted by the highly conserved nature of the acetylcholine site across mAChR subtypes. However, current efforts by our laboratory and others have now focused on modulators that bind to allosteric sites on mAChRs, allowing these compounds to display unprecedented subtype selectivity. Over the past couple of decades, the discovery of small molecules capable of selectively targeting the M1 or M4 mAChR subtypes has allowed researchers to elucidate the roles of these receptors in regulating cognitive and behavioral disturbances in preclinical animal models. Here, we provide an overview of these promising preclinical and clinical studies, which suggest that M1- and M4-selective modulators represent viable novel targets with the potential to successfully address a broad range of symptoms observed in patients with AD and SZ.
muscarinic receptors; schizophrenia; Alzheimer’s disease
This Letter describes the continued optimization of an MLPCN probe molecule (ML137) with a focused effort on the replacement/modification of the isatin moiety present in this highly selective M1 PAM. A diverse range of structures were validated as viable replacements for the isatin, many of which engendered sizeable improvements in their ability to enhance the potency and efficacy of acetylcholine when compared to ML137. Muscarinic receptor subtype selectivity for the M1 receptor was also maintained.
Muscarinic acetylcholine receptor 1; M1; Allosteric; Positive allosteric modulator (PAM); ML137; VU0448350
This Letter describes the continued optimization of an MLPCN probe molecule M1 antagonist (ML012) through an iterative parallel synthesis approach. After several rounds of modifications of the parent compound, we arrived at a new azetidine scaffold that displayed improved potency while maintaining a desirable level of selectivity over other muscarinic receptor subtypes. Data for representative molecules 7w (VU0452865) and 12a (VU0455691) are presented.
Muscarinic acetylcholine receptor 1; M1 Antagonist; ML012; VU0455691; VU0452865
This letter describes the further exploration of two series of M1allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M1 allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M1 allosteric agonist family (VU0357017) identified similar, subtle ‘molecular switches’ that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M1 activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism.
TBPB; M1; Allosteric agonist; Muscarinic receptor
Herein we report a next generation muscarinic receptor 4 (M4) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC50 = 56 nM) and rat (EC50 = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (Fold Shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.
Muscarinic receptor 4; Positive allosteric modulator; Amphetamine induced hyperlocomotion; CNS; PAM
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca2+ mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC50 of approximately 1.16 µM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
We previously reported the discovery of VU0364572 and
VU0357017 as M1-selective agonists that appear to activate
M1 through actions at an allosteric site. Previous studies
have revealed that chemical scaffolds for many allosteric modulators
contain molecular switches that allow discovery of allosteric antagonists
and allosteric agonists or positive allosteric modulators (PAMs) based
on a single chemical scaffold. Based on this, we initiated a series
of studies to develop selective M1 allosteric antagonists
based on the VU0364572 scaffold. Interestingly, two lead antagonists
identified in this series, VU0409774 and VU0409775, inhibited ACh-induced
Ca2+ responses at rat M1–5 receptor subtypes,
suggesting they are nonselective muscarinic antagonists. VU0409774
and VU0409775 also completely displaced binding of the nonselective
radioligand [3H]-NMS at M1 and M3 mAChRs with affinities similar to their functional IC50 values. Finally, Schild analysis revealed that these compounds inhibit
M1 responses through a fully competitive interaction at
the orthosteric binding site. This surprising finding prompted further
studies to determine whether agonist activity of VU0364572 and VU0357017
may also engage in previously unappreciated actions at the orthosteric
site on M1. Surprisingly, both VU0364572 and VU0357017
completely displaced [3H]-NMS binding to the orthosteric
site of M1–M5 receptors at high concentrations.
Furthermore, evaluation of agonist activity in systems with varying
levels of receptor reserve and Furchgott analysis using a cell line
expressing M1 under control of an inducible promotor was
consistent with an action of these compounds as weak orthosteric partial
agonists of M1. However, consistent with previous studies
suggesting actions at a site that is distinct from the orthosteric
binding site, VU0364572 or VU0357017 slowed the rate of [3H]-NMS dissociation from CHO-rM1 membranes. Together,
these results suggest that VU0364572 and VU0357017 act as bitopic
ligands and that novel antagonists in this series act as competitive
orthosteric site antagonists.
Acetylcholine; GPCR; allosteric; orthosteric; agonist; antagonist
Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu2 and mGlu3) and the group I mGlu5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu2 and mGlu3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor’s response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu2 and mGlu5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.
metabotropic; glutamate; schizophrenia; NMDA; allosteric
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu5 PAM chemotype.
metabotropic glutamate receptor 5; mGlu5; positive allosteric modulator (PAM); non-MPEP
Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
Metabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; nicotine self-administration; rat model; addiction
The M1 muscarinic acetylcholine receptor is
to play an important role in memory and cognition, making it a potential
target for the treatment of Alzheimer’s disease (AD) and schizophrenia.
Moreover, M1 interacts with BACE1 and regulates its proteosomal
degradation, suggesting selective M1 activation could afford
both palliative cognitive benefit as well as disease modification
in AD. A key challenge in targeting the muscarinic acetylcholine receptors
is achieving mAChR subtype selectivity. Our lab has previously reported
the M1 selective positive allosteric modulator ML169. Herein
we describe our efforts to further optimize this lead compound by
preparing analogue libraries and probing novel scaffolds. We were
able to identify several analogues that possessed submicromolar potency,
with our best example displaying an EC50 of 310 nM. The
new compounds maintained complete selectivity for the M1 receptor over the other subtypes (M2–M5), displayed improved DMPK profiles, and potentiated the carbachol
(CCh)-induced excitation in striatal MSNs. Selected analogues were
able to potentiate CCh-mediated nonamyloidogenic APPsα release,
further strengthening the concept that M1 PAMs may afford
a disease-modifying role in the treatment of AD.
Muscarinic; acetylcholine; positive allosteric
modulator (PAM); ML169; Alzheimer’s disease
(AD); medium spiny neurons (MSNs); MLPCN