Monday, 8 December 2014
Drug discovery and development in neuroscience is notoriously difficult. There are many reasons why this is the case, but key among them is the complexity of brain physiology and a general lack of translatable animal models in which to test new compounds.
As a result, brain disorders are often seen as a risky area for pharmaceutical companies.
AstraZeneca’s Neuroscience iMed manages our Central Nervous System and Pain programmes from target identification through to Phase II trials and is built almost entirely around a partnering model. In this concept, most of the laboratory work is not done in-house, but instead at the institutions of our many collaborators. It therefore brings together the outstanding science of the biotech and academic worlds with the research and commercial reach of AstraZeneca.
Importantly, this does not make us scientifically passive. We have an active role in directing the work that is done and can access internal expertise and laboratory support whenever necessary. However, the model does make us more nimble, because we can work with experienced, external partners in whichever fields of study we choose to enter. It also makes us very busy, as we currently oversee more than 20 ongoing projects!
The Vanderbilt collaboration
A great example of this model working successfully is our partnership with the Vanderbilt Center for Neuroscience Drug Discovery (Vanderbilt University, Nashville, TN, USA). We are working with Vanderbilt to develop positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) – a potentially important target underlying the cognitive impairments and behavioural disturbances associated with various neuropsychiatric disorders, including schizophrenia, Alzheimer’s disease and Parkinson’s disease.
Although based in an academic setting, the Vanderbilt group has vast industrial experience, so they understand the objectives and timelines of the pharmaceutical sector. Some might see the physical separation between the AstraZeneca and Vanderbilt teams as a challenge, but we believe we have turned it into an advantage, by allowing the intellectual independence of the two groups to generate complementary ideas.
When the collaboration was initiated in 2013, the Vanderbilt team already had an excellent data package for various M4 PAMs, including proof of concept in animal models.
Prior to the development of these compounds, the major problem in this area had been the close homology between the acetylcholine (ACh) binding sites of the five mAChR subtypes, M1–M5 (Jakubik et al. 2014). As a result, it was difficult to avoid off-target adverse effects with modulators targeting the ACh binding site of the M4 receptor. We are particularly excited by the potential of Vanderbilt’s ground-breaking new M4 PAMs because they are allosteric potentiators – in other words, they bind at a location that is separate from the ACh binding site, and where there is less homology between the various mAChRs. Hence, there is potential to achieve greater selectivity.
However, the big question is: can the M4 PAMs also provide sufficient potency to complement their selectivity? As shown in a recent publication, the answer seems to be ‘yes’ (Bubser et al. 2014). Furthermore, the lead compound was also shown to improve behavioural, cognitive, and neurochemical impairments in a mouse model (Bubser et al. 2014).
The future of the M4 PAMS
It is important to stress that this work is entirely preclinical and none of the M4 PAMs developed in collaboration with Vanderbilt have yet been tested in humans. A key next step will be to decide which neurological diseases offer the greatest potential for human studies of these compounds. Several conditions might benefit from an agent that mitigates behavioural disturbances, and preclinical studies are ongoing to help us make ‘go, no go’ decisions in Alzheimer’s disease, Parkinson’s disease and schizophrenia. Watch this space for further developments!
- Bubser et al. (2014). Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents. ACS Chem Neurosci 5(10):920-42.
- Jakubik et al. (2014). Outline of therapeutic interventions with muscarinic receptor-mediated transmission. Physiol Res 63 Suppl 1:S177-89.