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.
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 
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 
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 
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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.