Available treatments for Alzheimer’s disease offer relatively small symptomatic benefits and more effective treatments are much needed. β-Amyloid has been implicated in the pathogenesis of Alzheimer’s disease and much attention has focussed on inhibiting two enzymes responsible for production of this peptide, the β- and γ-secretases. Although potent inhibitors of both enzymes have been identified, achieving robust activity in animal models and progression to clinical studies has proved more challenging. Using a high-throughput functional genomics screen, scientists at VIB and Galapagos Pharmaceuticals have now identified a constitutively expressed orphan G protein-coupled receptor, GPR3, as another modulator of β-amyloid production. GPR3 is highly expressed in areas of the brain associated with Alzheimer’s disease and levels are elevated in brain tissue from people with sporadic Alzheimer’s disease. The researchers showed that blocking GPR3 prevented accumulation of β-amyloid, both in cell culture experiments and in a mouse model of Alzheimer’s disease.
Since G protein-coupled receptors have been relatively easy to exploit as drug targets, the scientists hope that GPR3 will prove to be a promising target for the treatment of Alzheimer’s disease.
The study is published in the February 13th issue of the journal Science.
Our sense of taste is critical for evaluating which substances are good to eat, and its importance is recognised in the many metaphors that surround the four tastes traditionally recognised in the West: a sweet melody, the souring of a relationship, bitter enemies, and salt of the earth. In 1908, a Japanese scientist, Kikunae Ikeda, recognised a fifth taste which he called umami, meaning “deliciousness”. Umami is a pleasant savoury taste that results from the detection of glutamic acid or glutamates which occur in protein-rich foods such as meat, cheese, and seafood. A truncated form of the metabotropic glutamate receptor, mGluR4 (taste mGluR4), and a heterodimeric (T1R1/T1R3) taste receptor complex have both been linked to the sensation of umami.
The umami taste triggered by L-glutamate is known to be dramatically enhanced by 5’ ribonucleotides, such as 5′-inosine monophosphate and guanosine 5′-monophosphate, and a new study describes the mechanism underlying this synergy. Scientists from Senomyx and BioPredict used chimeric T1R receptors, site-directed mutagenesis and molecular modelling to devise a cooperative ligand-binding model in which L-glutamate binds close to the hinge region of the ‘Venus flytrap’ (VFT) domain of T1R1, and the 5′ ribonucleotide binds to an adjacent site to further stabilize the closed conformation.
Allosteric modulators are attractive as drug candidates, especially since these might be expected to afford greater subtype selectivity in the case of closely related receptors that share the same ligand, such as mGluRs. Positive allosteric modulators, which have an effect only when the natural ligand is present in vivo, also have the potential to reduce side effects that could occur with constitutively active agonists. Identification of the L-glutamate and 5′-inosine monophosphate binding sites on the VFT domain of T1R1 may facilitate the development of allosteric modulators of other family C GPCRs as well as the development of new flavour enhancers.
The use of cannabis for ritual or medicinal purposes can be traced to prehistory, although today its use is controversial. Cannabinoids, the active constituents of cannabis, were first discovered in the 1940s but it wasn’t until the 1980s that the receptors for these plant substances were identified. There are two known cannabinoid receptors, CB1 and CB2. CB1 receptors are found primarily in the brain and appear to be responsible for the euphoric and anticonvulsive effects of cannabis whereas CB2 receptors are found almost exclusively in cells of the immune system. More recently, the endogenous lipids, 2-arachidonoylglycerol and anandamide, have been found to bind to cannabinoid receptors. Studies have revealed a broad role for endocannabinoid signalling in a variety of physiological processes including appetite, pain sensation, inflammatory response, mood and memory. An article in Nature Chemical Biology now further elucidates these pathways.
Signalling by endocannabinoids is terminated by enzymatic hydrolysis which, for anandamide, is mediated by fatty acid amide hydrolase and, for 2-arachidonoylglycerol, is thought to involve monoacylglycerol lipase; selective inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase would allow a better understanding of the roles of the two endocannabinoids. Inhibitors of fatty acid amide hydrolase have been available for some time, and have been shown to reduce pain, inflammation and anxiety by increasing levels of anandamide. For the first time, a selective inhibitor of monoacylglycerol lipase, JZL184, has now been identified. When administered to mice, JZL184 increased levels of 2-arachidonoylglycerol in the brain by about 8-fold, with no effect on levels of anandamide. Treatment with JZL184 produced analgesic effects similar to those achieved with fatty acid amide hydrolase inhibitors, but also produced other effects associated with CB1 agonism, namely hypothermia and hypomotility. If these effects can be controlled, inhibition of monoacylglycerol lipase may provide an alternative means of modulating the endocannabinoid system to alleviate pain.
Hearing loss is one of the most common conditions affecting older adults; more than half of people over the age of 60 are hard of hearing or deaf. The causes of age-related hearing impairment, also known as prebycusis, have not been fully established but it is known that the condition seems to run in families. Now a whole genome association study has linked GRM7, the gene encoding metabotropic glutamate receptor type 7 (mGluR7), with prebycusis. The study, published in Human Molecular Genetics identified variants in GRM7 in individuals with hearing loss. Follow-up histochemical studies in human and mouse showed that mGluR7 is expressed in hair cells and spiral ganglion cells of the inner ear. The data link common alleles of GRM7 to an individual’s risk of developing prebycusis, possibly by altering susceptibility to glutamate excitotoxicity. The identification of a genetic cause for age-related hearing loss could lead to the development of treatments for the condition, although the next step will be to develop an animal model to test potential treatments.
Cigarette smoking is recognised to be a major risk factor for disease, but once started, the habit is hard to quit. Nicotine is mainly responsible for dependence on tobacco and, historically, nicotine addiction has been one of the hardest to break. Now scientists at Scripps Florida have found that blocking the orexin A receptor in animal models abolishes the stimulatory effects of nicotine on brain reward circuitries and significantly reduces the desire for nicotine. In the study, the selective orexin A receptor antagonist, SB-334867, was found to decrease nicotine self-administration in rats and also reduced motivation to seek and obtain the drug.
If Orexin A is also involved in sustaining nicotine addiction in human smokers, blocking the orexin A receptor could be a potential target for developing new smoking cessation treatments. The Scripps group are hoping to discover new orexin A antagonists that would help smokers quit the habit. The study was published in the Nov 24 online Early Edition of the Proceedings of the National Academy of Sciences.
The orexin A receptor appears to be widely involved in regulating motivated behaviour and other studies have shown that SB-334867 also reduces alcohol-seeking behaviour in rats.
Collaborating scientists at the Scripps Research Institute and The Amsterdam Center for Drug Research have determined the crystal structure of the human adenosine A2A receptor, also known as the caffeine receptor. The receptor is a member of the hetero-trimeric G-protein coupled receptor (GPCR) superfamily and plays an important role in mediating responses to adenosine in many physiological processes. The scientists were able to obtain crystals of the protein by binding it to a potent adenosine antagonist, ZM241385, which had been developed as a potential drug to combat Parkinson’s disease. Full details have been published in the journal Science.
Despite the importance of GPCRs as drug targets, determination of their crystallographic structure has proven difficult. This new structure follows the success of the Scripps team’s publication of the β2-adrenergic receptor structure last year.
Adenosine interacts with a number of GPCRs including the A1, A2A, A2B, and A3 subtypes. Each of these plays a role in responding to adenosine in the central nervous system in pain regulation, cerebral blood flow, basal ganglia functions, respiration, and sleep. Insights obtained from the study of the A2A structure have already suggested mechanisms for receptor subtype selectivity.
It is hoped that this new information will help in the design of new drugs that could be important in the treatment of numerous neurological disorders, including Parkinson’s and Huntington disease.
Over 150 million people are estimated to be infected with the Hepatitis C virus. During the early stages of infection, the majority of people are free of symptoms but a significant number will later develop cirrhosis and possibly liver cancer.
Treatment is currently a combination of pegylated interferon-α and ribavirin, although several alternative therapies are being developed. Some of the more promising amongst these directly target essential viral enzymes such as the viral protease and polymerase.
The non-structural protein NS4B is an integral membrane protein that also plays a critical role in viral replication.
A new report shows that NS4B binds to viral RNA and describes the use of high-throughput microfluidic screening to identify compounds that inhibit this binding. 18 compounds that substantially reduced NS4B binding to its target RNA were discovered, and one of these compounds, clemizole, was found to inhibit replication of Hepatitis C virus in cell culture whilst showing little cellular toxicity.
Clemizole is an H1 histamine receptor antagonist and, because it has already been tested in people, it could be rapidly evaluated as a treatment for Hepatitis C infection.
Schizophrenia is a complex disorder, generally believed to arise from dysregulation of dopamine and glutamate neurotransmission pathways. Current front-line treatment comprises the atypical antipsychotics, which provide symptomatic relief but are associated with significant side-effects. These agents are broad-spectrum GPCR antagonists that act primarily at the dopamine and serotonin receptors.
Muscarinic acetylcholine (mACh) receptors regulate dopamine levels in areas of the brain associated with psychosis, with the M4 subtype speculated to be a key regulator of dopaminergic hyperactivity. The absence of subtype-selective modulators has, however, hindered validation of this hypothesis. Now scientists at Lilly have reported (PNAS, 5th August 2008) a selective small molecule, LY2033298, that targets the M4 subtype.
The compound has been shown to act at an allosteric site on the receptor, potentiating agonist binding while having little effect on antagonist binding. The authors have further demonstrated in vivo activity in preclinical models that are predictive of antipsychotic drug effects.
A drug which failed to reach the market as a treatment for HIV/AIDS has recently been shown to improve the survival of mice infected with West Nile virus, a virus that can cause encephalitis. It is believed that the drug, AMD-3100, acts by allowing T-cells to cross the blood-brain barrier and combat virus infecting the brain.
The drug works by blocking the receptor for the chemokine, CXCR4, and was originally developed to prevent the syncytium-forming variant of HIV using this receptor to gain entry to cells. Clinical trials, however, failed to show robust anti-viral activity.
The CXCR4 receptor and its physiological ligand, SDF-1, are also involved in mobilisation of hematopoietic stem cells into the bloodstream. Genzyme has recently filed applications in the US and Europe for AMD-3100 (Mozobil™, plerixafor) to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma. Because patients receive high-dose chemotherapy, which destroys bone marrow, a stem cell transplant is needed after chemotherapy to replenish blood-forming bone marrow cells. Genzyme has been developing Mozobil since its acquisition of AnorMED in 2006.