Ionotropic AMPA and NMDA glutamate receptors are ligand-gated ion channels that mediate fast synaptic transmission in the brain and play a crucial role in learning and memory. Dysfunction of these ...receptors is believed to be associated with a number of neuropsychiatric disorders, including schizophrenia. As direct activation of these ionotropic receptors can lead to excitoxicity, allosteric modulation of these receptors could minimize side-effects to achieve better therapeutic efficacy. Our review here focuses on the allosteric modulation of the NMDA receptor. Endogenous glycine and D-serine both act as co-agonists on the strychnine-insensitive GlyB site on the NMDA receptor, and along with glutamate, co-activate the NMDA receptor. Forebrain synaptic glycine and d-serine levels are regulated by the Glycine Transporter-1 (GlyT1) and the arginine-serine-cysteine transporter-1 (Asc-1), respectively; in addition to D-serine metabolism by D-Amino Acid Oxidase (DAAO). Together, these processes prevent the GlyB site from being saturated by the high extracellular levels of brain glycine, and perhaps d-serine, in vivo. Blockade of NMDA receptors by phencyclidine induces schizophrenia-like symptoms with the associated cognitive deficits. It was proposed that: a) blockade of GlyT1 mediated reuptake of glycine, or b) inhibition of D-amino Acid Oxidase, or Asc-1 will elevate brain glycine, and D-serine to upregulate NMDA receptor functions via glycine and D-serine co-agonistic allosteric modulation of the GlyB sites on the NMDA receptor. These approaches may provide novel treatments to schizophrenia, provided that some of the known adverse effects associated with existing GlyT1 agents can be safely and adequately dealt with.
(-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo3.1.0hexane-4,6-dicarboxylic acid (LY404039) is a potent and selective group II metabotropic glutamate (mGlu)2 and mGlu3 receptor agonist for which its ...prodrug LY2140023 (1R,4S,5S,6S)-2-thiabicyclo3.1.0-hexane-4,6-dicarboxylic acid,4-(2S)-2-amino-4-(methylthio)-1-oxobutylamino-, 2,2-dioxide monohydrate has recently been shown to have efficacy in the treatment of the positive and negative symptoms of schizophrenia. In this article, we use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine (PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 mg/kg, i.p.)-induced increases in ambulations, distance traveled, and reduced time spent at rest. LY404039 reversed PCP (7.5 mg/kg i.p.)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 (10 mg/kg i.p.) on PCP and AMP-evoked behavioral activation were absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice, indicating that the activation of mGlu2 and not mGlu3 receptors is responsible for the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039. In contrast, the atypical antipsychotic drugs clozapine and risperidone inhibited PCP-evoked behaviors in both wild-type and mGlu2/3 receptor-deficient mice. These data demonstrate that the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039 in psychostimulant models of psychosis are mechanistically distinct from those of atypical antipsychotic drugs and are dependent on functional mGlu2 and not mGlu3 receptors.
Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response ...curve. DETQ, 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged 13-23-month-old (mo) hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson's disease.
•The D1 receptor PAM DETQ restored NOR in scPCP-treated hD1 knock-in mice.•The efficacy of DETQ on NOR was blocked by the D1R antagonist, SCH391660.•There was no inverted U-shaped dose response curve ...or tolerance in the NOR test.•Rivastigmine, with or without DETQ, reversed the deficit in NOR.•DETQ enhances ACh efflux in PFC and HIP in saline- but not scPCP-treated hD1 mice.
Diminished dopamine D1 stimulation may contribute to cognitive impairment in Alzheimer’s and Parkinson’s diseases, schizophrenia, and other neuropsychiatric disorders. However, orthosteric D1 receptor (D1R) agonists produce receptor desensitization and an inverted U-shaped dose-response curve, but positive allosteric modulators (PAMs) do not. We examined the cognitive effects of DETQ, a D1R PAM, in mice genetically modified to express the human D1 receptor (“hD1 mice”). Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, dosed seven days (subchronic), followed by withdrawal, produced a prolonged deficit in novel object recognition (NOR) memory, which was reversed by acute treatment with DETQ, with no evidence for an inverted U-shaped response. This was blocked by the D1R antagonist, SCH391660. Single doses of D1R agonists, SKF38393 and SKF82958, and the acetylcholinesterase inhibitor, rivastigmine, alone and the combination of subeffective doses of both DETQ and rivastigmine, also restored NOR in both subchronic PCP-treated in hD1 mice. DETQ increased cortical and hippocampal acetylcholine efflux after both acute and subchronic dosing in hD1 mice. Subchronic but not acute DETQ, inhibited glutamate and GABA efflux. DETQ-induced acetylcholine efflux was absent in subchronic PCP-treated mice, indicating that restoration of NOR in subchronic PCP-treated mice does not require cortical acetylcholine efflux. This is additional evidence that DETQ stimulates D1R without producing an inverted-U-shaped response curve and increases neurotransmitter release in the mPFC and HIP without causing tolerance. The ability of D1 PAMs to improve cognition in humans with neuropsychiatric disorders without evidence of tolerance or an inverted-U-shaped response curve needs to be established clinically.
Schizophrenia is a devastating chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Although the positive symptoms are relatively well controlled by current ...monoamine-based treatments for schizophrenia, these agents provide only modest efficacy against the negative and cognitive symptoms of the disease. Furthermore serious adverse events have been reported during treatment with antipsychotic drugs. Therefore, novel treatment strategies are needed that provide improved efficacy across the multiple symptom domains of schizophrenia and have improved tolerability/safety profiles. Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays an important role in physiological and pathological processes of the CNS. Group II metabotropic glutamate receptors (mGlu receptors), in particular, have been shown to modulate glutamatergic activity in brain synapses thought to be involved in the pathophysiology of schizophrenia. In recent years a number of selective mGlu2/3 receptor agonists and mGlu2 positive allosteric modulators have been disclosed with demonstrated efficacy in multiple animal models for schizophrenia. Consistent with predictions from pre-clinical animal studies, LY2140023 monohydrate, an mGlu2/3 receptor agonist prodrug, recently demonstrated evidence for antipsychotic activity in phase II proof of concept study. Although additional efficacy and safety studies are needed to understand the therapeutic potential of LY2140023, emerging preclinical and clinical data suggest that activation of group II mGlu receptors is a mechanistically novel and promising approach for the treatment of schizophrenia.
This article is part of a Special Issue entitled ‘Schizophrenia’.
► Schizophrenia is a devastating chronic psychotic disorder. ► Altered glutamate transmission is implicated in the pathophysiology schizophrenia. ► mGlu2/3 agonists and mGlu2 PAMs show efficacy in animal models of schizophrenia. ► LY2140023 demonstrated efficacy in a clinical trial for schizophrenia. ► Activation of mGlu2/3 is a mechanistically novel approach to treat schizophrenia.
Dopamine (DA) plays a key role in several central functions including cognition, motor activity, and wakefulness. Although efforts to develop dopamine receptor 1 (D1) agonists have been challenging, ...a positive allosteric modulator represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the dopamine receptor 1 positive allosteric modulator (D1PAM) mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al., 2021). Herein, we describe the effects of mevidalen on sleep and wakefulness in humanized dopamine receptor 1 (hD1) mice and in sleep-deprived healthy male volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent 3-100 mg/kg, orally (PO) fashion when measured during the light (zeitgeber time 5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice after prior sleep deprivation and delayed sleep onset by 5.5- and 15.2-fold compared with vehicle-treated animals, after the 20 and 60 mg/kg PO doses, respectively, when compared with vehicle-treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, and 75 mg) separated from placebo at the first 2-hour postdose time point with a circadian effect at the 6-hour postdose time point. Sleep wakefulness should be considered a translational biomarker for the dopamine receptor 1 positive allosteric modulator mechanism. SIGNIFICANCE STATEMENT: This is the first translational study describing the effects of a selective dopamine receptor 1 positive allosteric modulator (D1PAM) on sleep and wakefulness in the human dopamine receptor 1 mouse and in sleep-deprived healthy male volunteers. In both species, drug exposure correlated with sleep latency, supporting the use of sleep-wake activity as a translational central biomarker for D1PAM. Wake-promoting effects of D1PAMs may offer therapeutic opportunities in several conditions, including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders.
An amine-containing molecule called Compound A has been reported by a group from Bristol-Myers Squibb to act as a positive allosteric modulator (PAM) at the dopamine D1 receptor. We synthesized the ...more active enantiomer of Compound A (BMS-A1) and compared it with the D1 PAMs DETQ and MLS6585, which are known to bind to intracellular loop 2 and the extracellular portion of transmembrane helix 7, respectively. Results from D1/D5 chimeras indicated that PAM activity of BMS-A1 tracked with the presence of D1 sequence in the N-terminal/extracellular region of the D1 receptor, a unique location compared with either of the other PAMs. In pairwise combinations, BMS-A1 potentiated the small allo-agonist activity of each of the other PAMs, while the triple PAM combination (in the absence of dopamine) produced a cAMP response about 64% of the maximum produced by dopamine. Each of the pairwise PAM combinations produced a much larger leftward shift of the dopamine EC
than either single PAM alone. All three PAMs in combination produced a 1000-fold leftward shift of the dopamine curve. These results demonstrate the presence of three non-overlapping allosteric sites that cooperatively stabilize the same activated state of the human D1 receptor. SIGNIFICANCE STATEMENT: Deficiencies in dopamine D1 receptor activation are seen in Parkinson disease and other neuropsychiatric disorders. In this study, three positive allosteric modulators of the dopamine D1 receptor were found to bind to distinct and separate sites, interacting synergistically with each other and dopamine, with the triple combination causing a 1000-fold leftward shift of the response to dopamine. These results showcase multiple opportunities to modulate D1 tone and highlight new pharmacological approaches for allosteric modulation of G-protein-coupled receptors.
Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. ...It was found that the length of the linker at the C5 position greatly affected the potentials of these D1 PAMs as CYP3A4 inducers, and the level of induction correlated well with the activation of the pregnane X receptor (PXR). Based on the published PXR X-ray crystal structures, we built a binding model specifically for these THIQ-scaffold-based D1 PAMs in the PXR ligand-binding pocket via an ensemble docking approach and found the model could explain the observed CYP induction disparity. Combined with our previously reported D1 receptor homology model, which identified the C5 position as pointing toward the solvent-exposed space, our PXR-binding model coincidentally suggested that structural modifications at the C5 position could productively modulate the CYP induction potential while maintaining the D1 PAM potency of these THIQ-based PAMs.
DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all ...rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.
•The dopamine D1 potentiator DETQ was tested in humanized D1 mice and rhesus monkeys.•Actions of DETQ were dependent on endogenous dopaminergic tone.•DETQ displayed a behavioral profile consistent with central D1 receptor activation.•Neurochemical actions of DETQ support potential pro-cognitive effects.•D1 potentiators show promise for Parkinson's disease and other CNS disorders.
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