BioWorld International Correspondent

LONDON - Privately held 14TM Ltd. agreed to a collaboration with the U.S. National Institute on Drug Abuse to design and synthesize compounds for treating drug abuse and dependency. No financial details were disclosed, but 14TM will have full rights to any products arising from the research.

The work will involve Cambridge-based 14TM in designing both allosteric and orthosteric ligands to a range of G protein-coupled receptor (GPCR) targets identified by Bethesda, Md.-based NIDA, which then will fund biological assays of compounds that are generated.

Robert Bywater, CEO, told BioWorld International, "NIDA has passed us half a dozen interesting targets and we are working on them already." 14TM specializes in the structure and function of GPCRs and has developed a number of technologies that can be used in structure-based drug design, including active and inactive receptor models, phylogenic tools for prediction of subtype specificity and bioinformatics tools.

Part of the aim behind setting up 14TM was to apply the technology in treating drug addiction. "Although it is known GPCR targets are useful in inhibiting drug addiction, there are not a lot of companies doing this work." Bywater said. "Most companies want to get rich quick so they are chasing GPCR targets in obesity and so on."

The collaboration particularly is interested in finding allosteric modulators as a route to fine-tuning the effects of any treatments. "In the case of opioid receptors, we could gradually block the effects of opiates over time, or in the case of dopamine receptors, activate one subtype, or deactivate another," Bywater said.

The institute, Bywater said, "knows where to put the brakes on: The ultimate aim is that there will be no high, enabling addicts to break the cycle of addiction."

GPCRs are an important class of targets for existing marketed drugs, but most of those bind to the orthosteric site that is targeted by the endogenous ligand. An increasing number of GPCRs have been shown to possess alternative or allosteric binding sites that are spatially and pharmacologically distinct from the orthosteric site.

Existing blockers of opioid receptors, such as Naxolone and Naltrexone, target the orthosteric site, preventing uptake of opiate drugs to initiate a high, but also inhibiting spontaneous opioid receptor activity by endogenous peptides such as endorphins.

"People will only succeed in breaking addiction if they want to stop," Bywater said. "We want to get away from the heavy-duty approach to develop compounds that apply the brakes at the right point."

14TM will work with its partner Proteom Ltd., also of Cambridge. Proteom has in silico screening and ligand design systems that can be used to eliminate potential side effects and generate small, high-specificity chemical libraries.

"The deal we have with [the institute] is that they will do all the very expensive assay work, free of charge, and any resulting compounds will be owned by us," Bywater said. "I am convinced we can then find commercial partners, or we wouldn't be doing this."