Re-Examining the Barbiturates

Moderate affinity for GABAA

Barbiturates are thought to bind to GABAA receptor channels at a site that is distinct from the benzodiazepine one. By binding to this site, they potentiate the inhibitory action of GABA. Barbiturate affinity for this site on GABAA channels is relatively moderate (around 100 µM). Our analysis made here relates to compounds with affinities of 10 nM and less for their target. However, low nM activity is reported against the nicotinic acetylcholine receptor (nAChR), which is in the same ion channel family as the GABAA channel.

Delving into the details

It would be interesting to learn more about the barbiturate compounds that affect the nicotinic acetylcholine receptor. Details about the properties of any of the barbiturate compounds can easily be retrieved using Reaxys Medicinal Chemistry. Figure 5 illustrates the display data for the potent nicotinic acetylcholine receptor-targeting compound, amylbarbital. The in vitro efficacy assay results and their corresponding references are highlighted.

Re-Examining the Potential of Barbiturates Figure 5 | Elsevier Whitepaper
Figure 5. Detailed information about amylbarbital

Barbiturates: alternative targets

Analysis View can be used to show how the number of barbiturate substances and biological targets with quantitative bioactivity data varies depending on the pX threshold (Figure 6). The highest proportions of barbiturates with bioactivity data have a pX value of between 5.1 and 6.0.

Re-Examining the Potential of Barbiturates Figure 6 | Elsevier Whitepaper
Figure 6. Analysis View showing how the number of barbiturate compounds and associated biological targets varies with the pX values

Examining this data set further we can see that the majority of barbiturate compounds with a pX between 5.1 and 6.0 are active against the protease MMP target family (Figure 7). Interestingly, activity against other targets, such as aggrecanase and DNA gyrase, could provide new avenues for research into osteoarthritis drugs and antibacterials using barbiturates as the scaffold.

Re-Examining the Potential of Barbiturates Figure 7 | Elsevier Whitepaper
Figure 7. Analysis View showing how the number of barbiturate compounds active against each target with pX values between 5.1 and 6.0


Despite having been largely supplanted by benzodiazepines and new classes of hypnotics, the barbiturates are still an interesting group of compounds. This study demonstrates that in silico profiling using Reaxys Medicinal Chemistry efficiently and rapidly elucidates the polypharmacology of drugs with the classical barbituric acid scaffold. Such studies could be performed to revisit the mechanism of action or provide a starting point for research into alternative indications.

Essential drug discovery solution

Reaxys Medicinal Chemistry is an extensive database containing chemical information linked to in vitro and in vivo biological activities extracted from over 300,000 articles, 90,000 patents and 5,000 journals. More than 6 million chemical compounds are associated with their biological data (> 29 million bioactivity data points) and linked to information on 12,700 pharmacological targets, allowing the scientists to reveal connections between compounds, effects and targets. The data is indexed and normalized for maximum searchability and consistency.