Discuss how agents that target metabotropic glutamate receptors might be therapeutically useful drugs
Glutamate is the primary excitatory neurotransmitter of the CNS. It is therefore no surprise there is increasing frustration that few agents targeting metabotropic glutamate receptors (mGluRs) have been clinically approved, considering their therapeutic potential(2). The eight mGluRs diverge into three groups, assembling as homomeric or heteromeric dimers and function as class C GPCRs. The discovery of mGlu5’s 7TM domain while attached to a negative allosteric modulator (NAM) has been vital in the progression of modulating mGluRs allosterically for therapeutic purposes(3). PAMs and NAMs have proven to be more selective than orthosteric agonists/antagonists and modulation of the receptors still remains dependant on the binding of glutamate (or other orthosteric agonists/antagonists). mGluRs involvement in the plasticity phenomena has also been widely demonstrated in many regions of the brain(4). They are also widely distributed around the CNS with Group I mGluRs predominantly found post-synaptically while Group II and III being located both pre- and post-synaptically. The complex nature of their localisation around the body further enhances the opportunity for specialised therapeutic interventions.
Schizophrenia(SCZ) affects around 1% of the population and produces both positive and negative symptoms, causing cognitive dysfunction and disorganised thoughts. It is proposed that hypofunction of NMDARs and the functional crosstalk between 5HT2AR and mGlu2 at the thalamo-cortical synapse contribute to SCZ(5, 6). Restoring normal glutamatergic signalling through modulation of mGluRs is a novel approach for treating SCZ. Pomaglumetad methionil is the prodrug of LY404039, a mGlu2/3 heterodimer agonist which showed promising efficacy in patients who were relatively early in the progression of SCZ and not been previously treated with atypical antipsychotics. After performing well in phase 2 trials, it did not prove to be significantly better than placebos in subsequent studies (7, 8). Further analysis of these studies showed that some schizophrenic patients who had taken atypical antipsychotics were affected by the resultant inhibition of 5HT2AR and down-regulation of mGLu2 in the prefrontal cortex, hence affecting the results of the trial(9). Looking forward, mGlu5 PAMs show promise in treating SCZ, as mGlu5 receptors are functional partners of NMDARs at many synapses in the CNS(10). VU0409551 has shown to enhance NMDAR function and reverse neuroplasticity deficits in serine racemase knockout mice, which show similar neurochemical profiles to SCZ(11, 12). However, it is a “biased” PAM, which does not potentiate the modulation of NMDAR through mGLu5. This recent study implicated that there are mechanisms independent of NMDAR hypofunction involved(13). Further research is being done to determine how exactly mGlu5 PAMs are enhancing NMDAR function.
mGlu5 has also shown potential as a target for treatment of Alzheimer’s disease (AD). The amyloid-beta (A) neurofibrillary tangles, which are characteristic of AD, mediate the dysregulation of NMDA receptors (14, 15). Targeting the NMDA receptors with antagonists is not a viable option as there would be significantly adverse side-effects, therefore mGluRs become a more appropriate target due to their more modulatory nature (16, 17). As previously stated, mGlu5 interacts with NMDA receptors, most probably through the Homer/PSD95/Shank complex (18). mGlu5 antagonists have been proven to prevent AD learning deficits and A-induced dendritic spine loss (19). To further confirm mGlu5 antagonism as a source treatment for AD, mGlu5 agonists were shown to suppress LTP and increase LTD, the same outcome with A oligomers isolated from Alzheimer brains (20, 21). VU0477573 is a mGlu5 partial NAM, which has shown good efficacy and does not produce the adverse side effects usually associated with full NAM and antagonism of mGlu5 (22). It is still yet to be discovered how mGlu5/NMDAR and A-oligomers interact, with many studies showing PrPC required to be present for A to be able to affect mGlu5 control of synaptic plasticity (19, 21, 22). On the contrary, Balducci et al. (2010) proved this to be wrong and that PrpC is not required for A to impair cognition. Determining the interactions between A-PrpC-mGlu5 is the next barrier to overcome.
mGluRs are also a potential target for substance addiction, with numerous mGlu1 NAMs being used in preclinical trials. EMQMCM for example, interrupts nicotine-seeking behaviour in rats and interestingly even lowered lethality in cocaine overdoses(23, 24). The mGlu2 receptor has shown to play a critical role in drug dependence, where the loss of mGlu2 expression in rats results in increased alcohol consumption, implicating that positive modulation or activation of mGlu2 receptors is a viable approach to treat drug dependence(25). When activated, mGluR2 indirectly reduces dopaminergic transmission in the nucleus accumbens and negatively modulates excitatory glutamatergic transmission(26, 27). AZD8529 (an mGlu2 PAM), after being ineffective in trials for SCZ, has been effective in three separate studies, decreasing nicotine and alcohol self-administration(28). There has unfortunately not been significant advancement in the use of Group III mGluRs to reduce dopaminergic transmission. A study showed L-AP4, an agonist for all Group III receptors (4,6,7 and 8), inhibiting stimulated glutamate release. This implicated that group III receptors can also affect drug dependence through activation by an agonist or PAM (29). mGlu7 has a higher concentration of expression in the basal ganglia than any of the other group III mGluRs, it also has the lowest affinity to glutamate so is therefore only activated when glutamate concentrations are high(29, 30). AMN082 is a mGlu7 PAM which has shown to have a similar binding efficacy to that of L-AP4 and does not inhibit other mGluRs, showing promise as a potential tool to further perturb whether mGlu7 is an option for treatment (31).
Costing the US over a billion dollars per annum, depression is also an illness where mGluRs show promise as a target for therapy, glutamatergic hyperfunction being one of its primary mediators. Ketamine (NMDAR antagonist) has proven to be effective but has prevalent side-effects from routine use(32). mGlu5 NAMs are seen as an alternative to Ketamine, as mGlu5s are proven to interact closely with NMDARs as seen in(33). Basimglurant (RG7090) for example has shown promising results, showing antidepressant properties and does not interfere with monoamine neurotransmitter(NT) levels(34). It must be noted however that mGLu5 is important in memory and learning, and NAMs could interfere with the interactions between late-LTP and learning(35, 36). Interestingly, Acamprosate is a mGlu5 and NMDAR functional antagonist, but has been used as an anti-craving drug for alcoholics for more than 20 years without producing any considerable impairments to memory(37). mGlu2/3 homodimer antagonists function similarly to Ketamine, directly targeting mTor signalling, with LY341495’s (mGlu2/3 antagonist) antidepressant effects being completely inhibited by rapamycin(38). This study suggests that the antagonism of mGlu2/3 activates mTor signalling via potentiation of AMPA receptors, resulting in synaptogenesis in the prefrontal cortex. This enables a rapid and sustained antidepressant effect.
Hyperactive glutamate transmission is also well documented in Parkinson’s disease(PD). In the Basal Ganglia(BG), glutamate and dopamine(DA) transmission is oppositely regulated. In PD, when dopaminergic neurons are degenerated in the Substantia Nigra (SNc) this results in hyperfunctional glutamate activity. This glutamatergic transmission takes place in the sub thalamic nucleus(STN) and is believed to be a contributor to the motor deficits in PD(39). The primary form of therapy is currently L-DOPA, which results in L-DOPA-induced dyskinesias (LIDs), calling for a novel approach which specifically targets glutamate hyperfunction. mGlu4 is expressed at glutamatergic and GABAergic synapses in the global pallidus pars externa, which is an indirect pathway of BG circuitry(40). Positive allosteric modulation of mGlu4s here would reduce glutamatergic transmission at subthalamopallidal and striatopallidal GABAergic synapses, restoring balance in the motor circuit of the BG (41). VU0418506 is a mGlu4 PAM still under development which has shown a favourable pharmacokinetic profile in multiple studies(42). Through CODA-RET examination, it has been proven not to potentiate activity at mGlu2/4 heterodimers, which are expressed at the corticostriatal synapse involved in regulating motor function(43). These studies are concordant with the proposition that mGlu4 PAMs show antiparkinsonian activity at homomeric receptors.
Absence Epilepsy (AE) is a disorder causing short episodes of detachment from reality, characterised by spike-and-wave discharges(SWDs) during an electroencephalogram (EEG). While many drugs are available clinically for treatment, some patients are yet resistant. Different mGluRs are positioned in the cortico-thalamic network which underlies the SWDs associated with AE (44). A study by Huguenard and Kyuyoung (2014) shows that when presynaptic mGlu7 at inhibitory synapses are activated, between ventrobasal thalamic and reticular thalamic neurons, there is a dampening effect upon oscillations contributing to AE (45). Further evidence that mGlu7 is a good target in AE is that when uncoupled with proteins interacting with C-kinase 1 in mice, the subjects experience absence-like seizures (46). Both Group II mGluRs (1 and 5) have also been closely linked with AE, using WAG/Rij rats which provide a comparable genetic profile of AE (47). Exhibiting reduced activity of both mGlu5 and mGlu1 in the cortico-thalamic circuit, using PAMs for both receptors showed a decrease in SWD frequency in the rats (35, 44, 48). Also, the mGlu 5 PAM VU0360172 did not show any tolerance being developed, suggesting this avenue of treatment for AE is viable(49).
mGluRs have shown promise therapeutically across their spectrum of their functionality, in various locations of the CNS. Perhaps the most encouraging development is the development of the mGlu5 PAM VU0409551 in the treatment of SCZ, which produces robust in vivo efficacy, without coupling to NMDAR function. This removes the unfavourable seizure activity seen with other unbiased mGlu5 PAMs when agonists bind(50). Further exemplifying the progress made with mGluRs is the development of VU0418506 in treatment of PD, however also recent progress to address the use of mGlu5 NAMs cooperatively with L-DOPA has been made(51). It is clear further progress has to be made, notably in the treatment of fragile X syndrome, where mGluRs have been linked but their role not being fully understood(52). It is also clear that mGlu5 has a significantly greater potential therapeutically compared to the entirety of the Group III receptors, which in comparison is a relatively unchartered area. While progress has been slow on the mGluR frontier since their discovery almost 30 years ago, there is still optimism they will eventually become a significant target for treatment on many fronts.