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Pharmacology of the nervous system > Metabotropic receptors: therapeutics > Flashcards

Metabotropic receptors: therapeutics Flashcards

1
Q

What are some conditions that might be treated by targeting mGluRs?

A

mGlu5 PAMs:
Schizophrenia (+ mGlu2/3 NAMs), Anxiety (+ mGlu2 NAMs)

mGlu5 NAMs:
Parkinson’s (+ mGlu4 PAMs), Fragile X syndrome, chronic pain (+ mGlu1 NAMs), GORD,
depression

Others: epilepsy, addiction, brain tumours, malignant melanoma

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2
Q

What is Fragile X syndrome?

A

Leading genetic cause of cognitive disability, also linked to autism

For years; mGlu5 NAMs predicted to be useful treatment, reached phase II trials (failed) - still returning to this but generally stopped

*most of the other diseases still being investigated

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3
Q

What is the role of mGluR subtypes in control of pain transmission?

A

mGlu1 + mGlu5 expressed on peripheral nociceptors, dorsal horn neurons + in pain centres in the brain such as the amygdala & thalamus

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4
Q

Role of mGluRs in pain at dorsal horn?

A

NMDARs on DH neurons important for transmission + show activation in chronic pain conditions - responsible for some chronic pain inflammation / hyperalgesia

Also mGlu1 / mGlu5 on this synapse: activation can UP-REGULATE NMDARs - therefore Group I mGluRs could increase NMDAR activation + contribute to hyperalgesia?

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5
Q

Role of mGluRs in pain at peripheral nociceptors?

A

Peripheral mGlu1 + mGlu5 activated by ambient Glu → nociceptor sensitisation to noxious heat

MCPG (orthosteric competitive mGlu1/5 antagonist) blocks cumulative pain response (wind-up) evoked by repetitive stimulation of the dorsal root

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6
Q

What are some other example of developing drugs acting on mGluRs for pain?

A

mGlu5 NAMs inhibit development of tolerance to morphine-induced analgesia

MPEP (mGlu5 NAM) blocks hyperalgesia in inflamed rat hind paw model of inflammatory pain

Promising phase II trial: mGlu5 NAM - efficacy for acute pain associated with migraine

  • may get licensed compounds that inhibit mGlu1/5 for treating pain
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7
Q

What is the role of mGluRs in anxiety? Evidence for this?

A

Rat line with spontaneous loss of mGlu2 discovered (premature stop codon; reduced mGlu2 expression) - show anxiety phenotype

  1. Elevated plus maze: mGlu2 KO spent less time in open arms, fewer entries + slower latency (how long until first enters arm)
  2. Hippocampal slices (measure AMPA EPSP then add mGlu2 LY agonist): controls show pre-synaptic Gi coupled decrease in Glu release, but KOs don’t (confirming mGlu2 absence)
    * animals found by accident - not all lab animals are the same
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8
Q

What are the approaches to treating anxiety by targeting mGluRs

A

mGlu2 PAMs

mGlu5 NAMs

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9
Q

How have mGlu2 PAMs been effective in anxiety models?

A

Johnson et al (2005): CBPiPES injection attenuates stress-induced hyperthermia - thought to be affect on anxiety rather than direct effect on temp

*CBiPES = mGlu2 PAM that increases potency of orthosteric agonists such as glutamate (left shift in CRC)

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10
Q

How have mGlu5 NAMs been effective in anxiety models?

A

MPEP (mGlu5 NAM) also reduces stress-induced hyperthermia

*FENOBAM, clinically validated anxiolytic + shown to be selective mGlu5 NAM

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11
Q

What is Parkinson’s disease?

A

Neurodegenerative disease = decrease in number of cells in substansia nigra, less dopamine released in certain areas of brain - movement disorder + cognitive decline

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12
Q

What is the role of mGluRs in Parkinson’s disease?

A

mGlu4 activation hypothesised to restore balance to inhibitory output to the thalamus thereby correcting movement disorders

May slow disease progression by reducing excessive glutamate release onto dopaminergic neurons in substansia nigra thereby protecting them from excitotoxicity

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13
Q

What drugs have been tested in Parkinson’s models?

A

Injected haloperidol (D2 antagonist) into rat ventricles to mimic the DA reduction in PD

VU… = PAM of mGlu4 receptors

  • dose-dependent decrease in catalepsy (Niswender et al 2008)
  • also protects cultured neural stem cells from damage from free radicals (Zhang et al 2015)
  • may be triggering another pathway to promote cell survival, rather than just regulating glutamate release
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14
Q

What is schizophrenia?

A

Psychiatric illness: affects ~1% worldwide. Positive symptoms: hallucinations, delusions & thought disorder. Negative symptoms: social withdrawal, apathy, emotional blunting

Patients also suffer cognitive deficits e.g. attention, LTM & STM

Clinically effective antipsychotics are D2 and 5-HT2A antagonists (e.g. olanzapine) - disorder therefore thought to involve imbalance in dopamine transmission

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15
Q

How do current schizophrenia treatments act?

A

Clinically effective antipsychotics are D2 and 5-HT2A antagonists (e.g. olanzapine) - disorder therefore thought to involve imbalance in dopamine transmission

Effective in treating positive symptoms but at best have only modest effects on negative symptoms and cognitive impairment

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16
Q

Role of NMDArs in schizophrenia? Why/evidence?

A

Hypofunction thought to lead to increased glutamatergic transmission in pre-frontal cortex: psychosis

High affinity NMDAR blockers such as PCP (also bencyclidine?) produce state of psychosis in humans (&animals) + exacerbate symptoms in patients

KO NMDAR mice show some supposed schizophrenia symptoms e.g. social isolation but difficult to say if this relates to human disorder (can’t be sure if a mouse is having delusions/hallucinations etc.)

17
Q

Role of glutamate receptors in schizophrenia? Why/evidence?

A

NMDAR activation on GABAergic interneurons: inhibitory control on excitatory glutamatergic thalamocortical neurons that project to pyramidal neurons in the prefrontal cortex (PFC)

Therefore NMDAR hypofunction = increased excitation of PFC (disinhibition)

Hypofunction or blockade (e.g. with PCP) of NMDARs leads to disinhibition of thalamocortical glutamatergic neurons that provide excitatory input to pyramidal neurons in the PFC

18
Q

In schizophrenia, what does overactivation of glutamatergic neurons cause?

A

Excessive AMPA/KAR activation on cortical neurons

Enhanced excitability of PFC neurons & enhanced downstream Glu release by cortex → excites 5HT & DA neurons in the midbrain

  • 5HT/DA midbrain neurons release more 5HT/dopamine (excited by cortex) → involved in control of the thalamic input back into the cortex

Activation of 5HT2A receptors in PFC leads to enhanced Glu release, activation of AMPARs/KARs + hyperexcitability of neurons in the PFC

19
Q

Where are 5HT and DA antagonists most likely acting in schizophrenia treatment?

A

The synapse from 5HT / DA neurons in midbrain onto thalamic/hippocampal glutamatergic neurons (which drives glutamate release onto cortex)

20
Q

Where do hallucinogens act?

A

Hallucinogens e.g. DOI usually interact with 5HT2 receptors on thalamic/hippocampal neurons, to excite the neurons and cause glutamate release to induce schizophrenia symptoms

21
Q

How may drugs that enhance NMDAR activity help schizophrenia?

A
  1. Enhancing activity at GABAergic interneurons to normalise inhibitory control improve cognition
    * mGlu5 PAMs (mGlu5 located on GABAergic interneurons expressing NMDARs)
    * NMDAR PAMs (reinstating GABAergic inhibition of glutamateric thalamic neurons)
    * GlyT-1 inhibitors or D-amino acid oxidase inhibitors could help potentiate NMDARs if glycine not saturated
  2. mGlu2/3 agonists (post-synaptic) can potentiate NMDAR function
  3. Orthosteric mGlu2/3 agonists (e.g. LY…) or mGlu2 PAMs (e.g. CBiPES) interacting with pre-synaptic receptors where thalamic neurons synapse with cortex + midbrain, and at pre-synaptic receptors where cortex synapses with midbrain- would reduce excessive glutamate release
    * mGlu2/3 agonists also have neuroprotective properties
22
Q

mGlu5 PAMs and schizophrenia - evidence?

A

CHPG (orthosteric mGlu5 agonist) potentiates NMDA-induced currents in CA1 neurons + in forebrain + midbrain circuits (areas relevant to schizophrenia)

Potentiation of NMDAR-dependent LTP by mGlu5 PAMs - beneficial for positive symptoms + cog deficit?

mGlu5 PAMs improve cog performance + antipsychotic activity in animal models

BUT; potentiation of NMDAR responses may also lead to excitotoxicity & epileptogenesis

  • aim: boost NMDAR function in particular neurons with hypofunction
23
Q

Future aim for mGlu5 PAMs in schizophrenia?

A

Biased mGlu5 PAMs that retain antipsychotic activity through modulation of signalling pathways downstream of NMDAR activation but avoid pathways leading to adverse effects / cell death have potential as treatment for schizophrenia

24
Q

Evidence for use of mGlu2 PAMs in schizophrenia?

A

PCP = high affinity (non-competitive) NMDA channel blocker, induces schizophrenic-like symptoms: hyperlocomotor activity in mice - models agitation & repetitive movements seen in patients with schizophrenia

mGlu2 PAM CBiPES significantly reduced PCP-induced hyperlocomotor activity in mice

This response of CBiPES was blocked by competitive group II antagonist (LY3…)

Limitation: not a great model of schizophrenia (but atypical antipsychotics are also effective in PCP model of psychosis)

25
Q

What is LY404039

A

Orthosteric mGlu2/3 agonist (gone the furthest in clinical trials for schizophrenia) - but low oral bioavailability in humans

LY2140023 = methionine amide of LY404039 - effective oral prodrug in humans, rapidly converted into LY404039 producing a sustained level of the drug in plasma
*peak in prodrug levels then gets broken down - sustained increase in active drug

26
Q

What animal evidence has shown beneficial effects of LY404039?

A

Blocks PCP-induced hyper locomotion in mice (not as good as control levels but still a reduction) - but no effect in mice lacking mGlu2 + mGlu3

Confirms that mGlu2/3 is causing the reduction in symptoms

Olanzapine blocks PCP-induced hyperlocomotion in both WT and KO mice
(again not perfect reduction to control levels but still a reduction)

*Olanzapine produces antipsychotic effect by blocking 5-HT2A and D2 receptors whereas LY404039 activates mGlu2 + mGlu3

27
Q

What was a Phase 2 trial of LY404039?

A

Patil et al (2005)

Prodrug of LY404039 effective treatment of both positive & negative symptoms of schizophrenia (PANSS = positive and negative schizophrenia scale)

Placebo slightly increases score over time, olanzapine + prodrug both show reduction in PANSS score (prodrug not sig diff from olanzapine)

  • Side-effects such as prolactin elevation, extrapyramidal symptoms or weight gain not observed (weight gain in olanzapine)
  • Some patients exhibited increase in emotional response + memories of past emotionally important events - treatment may improve cognitive performance - not observed with atypical antipsychotics
28
Q

What was the 2nd Phase II trial of LY404039?

A

Adams et al (2013): Phase 2 in Humans

Comparing pro-drug with standard of care (SOC) - mixture e.g. olanzepine, rispiridone etc.

  • Prodrug reduces PANSS score, but reduction is bigger with SOC
  • Another Phase II (2014/2015) showed similar effect; one drug currently used was better than the mGlu2/3 agonist prodrug

Need big phase III trial to show if effective; as good at relieving schizophrenia symptoms / better for side effects

29
Q

How do mGlu2/3 agonists exert antipsychotic effects

A

Likely to be multiple mechanisms

Main = mGlu2/3 activation on terminals of thalamocortical neurones: blocks release of Glu + normalises excitatory input to PFC

mGlu2/3 agonists reduce Glu release in mesolimbic regions (e.g. nucleus accumbens) + indirectly reduce DA transmission

mGlu2 + 5HT2a form heterodimeric complex with different signalling properties to 5HT2a alone (5HT2a linked with schizoph. as inhibited by current drugs)

By reducing Glu release, may also protect against progressive neurodegeneation associated with schizophrenia (excessive glutamate release leads to neuronal cell death)

Activation of postsynaptic mGlu2/3 on CA1 neurons has shown to potentiate GluN2A-containing NMDAR function + this may help to counteract NMDAR hypofunction associated with schizophrenia

30
Q

What is the effect of stimulating 5HT2A receptors?

A

Induces 2 different signalling pathways:

  • Gq/11-mediated c-fos induction
  • Gi/Go mediated egr-2 induction

Gi/Go / ERG2 pathway is only induced by hallucinogens, linked to schizophrenia
*look at expression of the two proteins to see which pathway has been activated

31
Q

What is the effect of stimulating 5HT2A receptors?

A

Induces 2 different signalling pathways:

  • Gq/11-mediated c-fos induction
  • Gi/Go mediated egr-2 induction

Gi/Go / ERG2 pathway is only induced by hallucinogens, linked to schizophrenia
*look at expression of the two proteins to see which pathway has been activated

32
Q

Why is the mGlu2/3-5HT2A heterocomplex important in schizophrenia?

A

mGlu2 activation in the heterocomplex ONLY prevents hallucinogenic 5TH2A receptor-mediated egr-2 induction (not the non-hallucinogenic c-fos induction)

If have heterodimer between mGlu2/3 + 5HT2A - lose the hallucinogenic pathway as interaction with mGlu2/3 stops 5HT2A receptor signalling through this pathway

Prevention of hallucinogenic signalling through 5HT2A/mGlu2 heterocomplexes by mGlu2 receptor agonists may contribute to the therapeutic benefits of such compounds in schizophrenia

33
Q

What are the antipsychotic effects of mGlu2 / mGlu3 agonists? Further research needed?

A

Predominantely mediated by mGlu2

mGlu2 PAMs inhibit mGLu2/5-HT2A hallucinatory signalling - have antipsychotic properties in animal models are in early clinical development

LY404039 blocked PCP-induced hyperlocomotor activity in mice lacking mGlu3 but not in those lacking mGlu2 or both mGlu2 & mGlu3 receptors: mGlu2 needed for activity
- agonist has got the furthest so far, but could a PAM be better? PAMs haven’t got so far

Selective mGlu3 agonists and/or PAMs are needed to rule out a role for mGlu3 in schizophrenia

Pharmacology of the nervous system (9 decks)

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