Metabotropic receptors: therapeutics Flashcards
(33 cards)
What are some conditions that might be treated by targeting mGluRs?
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
What is Fragile X syndrome?
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
What is the role of mGluR subtypes in control of pain transmission?
mGlu1 + mGlu5 expressed on peripheral nociceptors, dorsal horn neurons + in pain centres in the brain such as the amygdala & thalamus
Role of mGluRs in pain at dorsal horn?
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?
Role of mGluRs in pain at peripheral nociceptors?
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
What are some other example of developing drugs acting on mGluRs for pain?
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
What is the role of mGluRs in anxiety? Evidence for this?
Rat line with spontaneous loss of mGlu2 discovered (premature stop codon; reduced mGlu2 expression) - show anxiety phenotype
- Elevated plus maze: mGlu2 KO spent less time in open arms, fewer entries + slower latency (how long until first enters arm)
- 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
What are the approaches to treating anxiety by targeting mGluRs
mGlu2 PAMs
mGlu5 NAMs
How have mGlu2 PAMs been effective in anxiety models?
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)
How have mGlu5 NAMs been effective in anxiety models?
MPEP (mGlu5 NAM) also reduces stress-induced hyperthermia
*FENOBAM, clinically validated anxiolytic + shown to be selective mGlu5 NAM
What is Parkinson’s disease?
Neurodegenerative disease = decrease in number of cells in substansia nigra, less dopamine released in certain areas of brain - movement disorder + cognitive decline
What is the role of mGluRs in Parkinson’s disease?
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
What drugs have been tested in Parkinson’s models?
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
What is schizophrenia?
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
How do current schizophrenia treatments act?
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
Role of NMDArs in schizophrenia? Why/evidence?
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.)
Role of glutamate receptors in schizophrenia? Why/evidence?
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
In schizophrenia, what does overactivation of glutamatergic neurons cause?
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
Where are 5HT and DA antagonists most likely acting in schizophrenia treatment?
The synapse from 5HT / DA neurons in midbrain onto thalamic/hippocampal glutamatergic neurons (which drives glutamate release onto cortex)
Where do hallucinogens act?
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
How may drugs that enhance NMDAR activity help schizophrenia?
- 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 - mGlu2/3 agonists (post-synaptic) can potentiate NMDAR function
- 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
mGlu5 PAMs and schizophrenia - evidence?
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
Future aim for mGlu5 PAMs in schizophrenia?
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
Evidence for use of mGlu2 PAMs in schizophrenia?
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)
