THuNDRous news for human dopamine researchers: A selective dopamine D1 receptor antagonist will soon be available for clinical research

Pre-clinical (basic animal-based) neuroscience has made enormous advances in recent decades, but human brain research lags behind, despite new imaging techniques such as positron emission tomography, functional magnetic resonance imaging and magnetoencephalography. The main reason for this is that, other than pre-existing medicines, there are very few selective compounds available for human experimental brain research. Pre-clinical researchers can simply order a selective chemical from a supplier and start an experiment within days. Moreover, when selective compounds are not available, they can turn to specific molecular techniques, e.g. short interfering ribonucleic acid, to produce the desired interference with the biological system in question. Human researchers do not have this option. Even when used as research tools, drugs need extensive safety testing and quality control before they can be given to humans. This process is extremely expensive and time consuming and has almost never been achieved other than for medicines. However, most medicines were not designed to be selective for specific brain receptors, so few are useful to interrogate specific receptor processes. In recent decades, pharmaceutical companies have made highly receptor-selective compounds as potential new treatments where selectivity is based on pre-clinical research. Often these fail in their primary therapeutic indications, but then for economic or strategic reasons they are discarded: modern pharmaceutical research has developed scores of selective compounds but almost none are available for human research.

This is a huge wasted opportunity because 1) other clinical indications cannot be examined and 2) the reasons for failure are rarely determined. As these compounds were developed based on pre-clinical research, this failure to explain the lack of clinical efficacy represents a major block in ‘back-translation’ to the detriment of the whole field. This extinction of ‘failed’ compounds means there are very few brain receptor-selective compounds available for human research. Currently the only selective agents available are clinical medicines: antagonists at the D2 receptor (amisulpride/sulpiride), an agonist at the noradrenaline α2-adrenoceptor (clonidine), plus the α1 subtype-selective benzodiazepine zolpidem. This problem has been known for some time and the ECNP Medicines Chest was set up to help rectify it (https://www.ecnp.eu/research-innovation/ECNP-medicines-chest.aspx). However, getting compounds into the chest has proved very difficult because most drugs of interest are no longer available in a form that is suitable for human use. They need re-synthesis to good manufacturing practice standards, which is very expensive, of the order of a million pounds per compound to include later storage and stability testing over 5 years or more.

Several years ago we approached the Wellcome Trust to support an initiative to improve the situation by their funding the re-synthesis of proven tool compounds that pharmaceutical companies were no longer developing, called Tools for Human Drug and Brain Research (THuNDR).

Our initial target was ADX10061, a highly selective antagonist for the dopamine D1 receptor, which has been used in human trials already (ADX10061 was previously known as CEE-310 and NNC-687; see Andersen et al., 1992; Skrumsager et al., 1995; Sugamori et al., 1998; Tice et al., 1994). The D1 receptor is the more prevalent dopamine receptor in the cortex and one that pre-clinical research shows is important in several brain functions. The key challenge, other than funding, was to obtain access to all the synthetic and regulatory (tox and pk) data from the company that owns them. Vitally, Addex, the company that owns ADX10061, gave us full access to their in-house know-how and regulatory documentation to re-synthesise ADX10061 in a form suitable for human research. We now have all the data necessary to allow us to carry out a clinical study once new supply of the drug has been made.

The grant we submitted to the Wellcome Trust was under the new Biomedical Resources programme. It was a collaboration of six leading UK human psychopharmacologists, Nutt, Robbins, Dodds, Mehta, Munafò and Browning. Critically, we also had to engage a group of technical experts from the pharmaceutical industry, led by Ann Hayes, who have the required skills in chemical production, analysis and testing, pharmaceutical preparation and dispensing, and drug development project management. Each of these skills is required for the production and distribution of ADX10061 under current regulatory requirements.

This grant will make available ADX10061 (+ matching placebo) in formulations with Medicines and Healthcare products Regulatory Agency-compatible documentation to allow its immediate use in human experiments. The Wellcome Trust support does not cover the costs of staff, scanning and running experiments as these will come from the applicants’ ongoing research programmes and future grants. The drug will effectively be made available at a low cost for all future studies – about £20,000 per study – so will be in the reach of almost all grant funders.

Moreover, THuNDR2 will reach beyond the current applicants. Other research groups in the United Kingdom, Europe and the United States have expressed an interest in obtaining ADX10061 for their own research projects. Initially this will be managed through the programme with the THuNDR2 management group, which will review applications and ensure the applying groups have the necessary skills and experience to conduct the experiments they propose and that these experiments will be appropriate for ADX10061. For those studies approved for compound supply, a legal agreement will then be negotiated between the academic institution and Addex; this will cover issues such as confidentiality, publication and ownership of intellectual properties. This follows the model already in place for the ECNP Medicines Chest initiative (https://www.ecnp.eu/research-innovation/ECNP-medicines-chest.aspx). Also, the Stanley Foundation, an international charity that funds much psychiatric and psychopharmacology research, has agreed to encourage research with ADX10061.

It is clear that THuNDR is a landmark biomedical resource from the Wellcome Trust that will provide a vital boost to human experimental neuroscience both in the United Kingdom and across the world for many years to come.