Schizophrenia – new targets?

Over the past decade too many psychiatric candidate drugs have hit the buffers, usually after making it to late phase clinical trials. This has made big pharma reluctant to invest in drugs for patients with mental illnesses. Jeffrey Conn, Nashville, Tennessee, explained how his lab operates to methodically work through the properties of candidate drugs to minimise the risks for pharmaceutical companies. Using a systematic iterative approach, with a weekly turnaround time from the creation of new candidate molecules to their suitability being tested in the lab – new candidate drugs that are highly-selective for M1 or M4 acetylcholine receptors (AchR) have been discovered.

Weekly chemical tweaks

How did they do it? Lab team members started the process by scanning a host of candidate M-type AchR molecules to identify 41 for further study. These were then sequentially analysed to investigate each molecule’s pharmacological properties and suitability to be taken forward for further testing. Those molecules showing the best properties were then tweaked by organic chemists and the newly synthesised drugs’ properties were then tested all over again. Each reiteration of this process takes just one week.

Targeted approach

Targeting M1- and M4-type AchR allosterically generates highly-specific modulators.

Why has this approach been so successful? Previously, scientists honed in on orthosteric parts of the different M-type AchRs. Put simply, they targeted the parts of the M-type AchR that sub-types had in common. This meant that there was some cross-reactivity between drugs meant to target either the M1- or M4-type AchR. Dr Conn’s lab, instead, has targeted parts of each M1- and M4-type AchR that are specific to that receptor type and in this way has generated allosteric modulators that are highly-specific to each receptor.

New highly-specific candidate psychiatric drugs created

Two candidates are of potential interest to psychiatry. One drug is a selective M1 positive allosteric modulator (PAM) and has been shown, in animal models, to rescue PCP disruption of M1-induced long-term depression. It also restores deficits in social cognition in chronic PCP-treated mice. This improvement in cognition without anti-psychotic effects is an exciting development and optimised MI positive allosteric modulators will be tested in humans in September 2016.

The second molecule is a selective M4 positive allosteric modulator. It shows robust efficacy in preclinical models predictive of anti-psychotic-like activity. This molecule is being co-developed with a pharmaceutical company as its properties are of obvious interest in the management of psychosis.

Pipeline

By adopting such a systematic approach to drug development, a pipeline of novel psychiatric drugs has been generated. The outcomes from the clinical studies these spawn are awaited keenly.