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AMN082 (N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride) is a selective metabotropic glutamate receptor 7 (mGluR7) allosteric agonist that was discovered by Mitsukawa and colleagues in 2005. It mimics the effect of glutamate. AMN082 is the first selective mGluR7]] agonist and has expanded the potential array of research opportunities on the effects of mGluR7 in the CNS.

Significance
The two main types of glutamate receptors are ionotropic receptors and metabotropic receptors. Ionotropic receptors (iGluRs) are fast-acting ligand-gated ion channels and include AMPA, Kainate, and NMDA receptors. Metabotropic receptors are G-protein coupled receptors that mediate slower, longer lasting effects through second messenger systems and are responsible for other neuronal functions that are not typically controlled by iGluRs, such as the direct inhibition or activation of adenylyl cyclase. mGluRs are split into 3 separate groups (Group I, Group II, Group III) based on pharmacological profile, sequence homology, and preferred signal transduction pathway. mGlur7 is a member of Group III, the least studied of the groups and are found on the presynaptic area of glutamatergic and GABAergic synapses. The discovery of AMN082 may serve as a useful pharmacological tool to expand research on Group III mGluRs and the ways in which mGluRs regulate and influence systems in the brain like the reward pathway and dopaminergic system and disorders like addiction, depression and anxiety, and Parkinson's Disease.

The Effect of AMN082 on the Cell
The metabotropic receptor mGluR7 has been shown to be an autoreceptor that is one of the most common receptors found in the CNS. As a Gi/o protein coupled receptor, mGluR7 inhibits the activation of adenylyl cyclase once a neurotransmitter (typically glutamate) has bound to this receptor. With the inhibition of adenylyl cyclase, mGluR7 slows this enzyme from being able to catalyze the reaction of ATP producing cAMP and pyrophosphate. The production of cAMP is crucial to the formation of memory through LTP and LTD and influences the onset of disorders like anxiety, depression, and bipolar disorder. AMN082 acts a selective allosteric agonist for mGluR7. AMN082 binds to and activates this receptor, causing the effective inhibition on adenylyl cyclase and, furthermore, the inhibition of accumulation of cAMP. Although all preclinical studies have been done in vivo in rats only, AMN082 seems to have the ability to readily pass through the blood-brain barrier with concentrations around 339g/g once it has been dissolved in a vehicle solution of distilled water and fluoxetine HCl, suggesting it might act as a prodrug to penetrate the blood-brain barrier. The ability to cross the blood-brain barrier also suggests that AMN082 has a strong affinity to its binding site, mGluR7. It has proven in multiple studies that AMN082 has the strongest affinity to mGluR7 out of other drugs that have been studied for selectivity of mGluR7, like orthosteric ligands DL-AP4 and L-glutamate, studied for glutamate receptor affinity--specifically for the affinity for mGluR7, with an EC50 of around 260nM, compared to an EC50 of around 540μM and 700μM for DL-AP4 and L-glutamate, respectively. AMN082 is a full agonist that binds to the transmembrane region of mGluR7, as opposed to the specified binding sight of much of the mGluR7 neurotransmission. In doing so, AMN082 has the ability to affect the binding of substrates to the receptor but in a noncompetitive way. AMN082 can be administered orally or intraperitoneally. When administered orally, the bioavailable doses are 0.29μmol/kg from a 10mg/kg dose and a 0.62μmol/kg from a 14mg/kg dose and the half-life of AMN082 tends to be less than 1 minute. The Kd is about 7.33nM and the Bmaxseems to have yet been determined. A metabolite of AMN082 is Met-1, this metabolite is significantly selective as an agonist for monoamine transporters including SERT, DAT, and NET receptors and about 100-fold less selective for mGluR7. While AMN082 is mostly saturable at mGluR7, it has a small but equal affinity for DAT and NET, Met-1, with a molecular weight of 226, has a 10-fold higher affinity to SERT. The Met-1 high affinity for SERT could be the influence the antidepressant effects of the drug, AMN082.

Possible Treatments
AMN082 is being studied as a treatment for many different diseases, including addiction to drugs like cocaine and morphine, depression, bipolar disorder, and other mental illnesses, and Parkinson's Disease. All of these treatment options are still in preclinical phases and many of the studies done continue to be done "in vivo" in rats and in CHO cells and occasionally on rats who have been genetically modified to include the human form mGluR7. It is important to note that studies have found that AMN082 could be safely taken orally, which makes for convenient and long-term treatment. The glutamatergic system has been shown to significantly influence the reward pathway of the brain, modulating the dopaminergic system. Because the glutamatergic system is so closely intertwined with the reward pathway with glutamatergic receptors and neurotransmission being in similar brain regions like the basal ganglia, amygdala, hippocampus, and hypothalamus it can be gleaned that a drug that influences mGluR7 could also the brain regions which in resides and the pathways that it influences, the reward pathway. This idea was further proven by the fact that AMN082 at doses of 10mg/kg attenuated both behavioral sensitization, the persistent increase in psychomotor activating effects and their incentive to motivating properties with persistent use of drugs, and cross-sensitization, the idea that combined use of drugs from different pharmacological classes can cause greater effect than use of a single drug by itself, of drug addiction. AMN082 has also been studied for its effects on depression and anxiety. It is well-established that serotonin and transmission of serotonin significantly influences the development of depression and anxiety. SSRI's are a common type of drug used to regulate the uptake of serotonin at the transporter SERT, which in turn produces positive outcomes for patients with disorders like depression and anxiety, but it has been found that AMN082 can also have significant antidepressant and anti-anxiety effects by allowing increased neurotransmission of serotonin, the hypothesis being that a lack of serotonin in the brain causing the symptoms of depression and anxiety. All studies were either done in rats or on CHO cells that were successfully transfected with human mGluR7α. These antidepressant and anxiety effects may be due to a combination of AMN082's agonizing affects but also Met-1, the major metabolite of AMN082, acting as an agonist on SERT.

Lastly, AMN082 is being researched as an effective treatment for Parkinson's Disease. Although dopamine treatments have increased the lifespan of PD patients, the side effects include abnormal involuntary movements. mGluR7 and other mGluR's have been known to help reverse this side effect in animals. The greater activation of mGluR's such as mGluR7 could lead to the reversing of the motor issues caused by dopamine deficits, AMN082 is a drug that increases the activation of mGluR7 making it a possible candidate for aiding in the reduction of motor symptoms for PD patients.

Side Effects of AMN082
AMN082 is found to cause extreme lessening in motor function at high doses in vivo in rats. In a study determining AMN082's affects on sleep and wakefulness, it was found also that, at low doses, it is possible that AMN082 causes an increase sleeping, specifically NREM sleep. At high doses, AMN082, has been shown to cause a decrease in both NREM and REM sleep, suggesting that at high doses, AMN082 could cause an inability to sleep.