Nature: Toxicity of drugs, understanding the structure of this protein can guide the safe use of drugs
Increased risk of mixed use
These drugs include diazepam, alprazolam, etc. They have been used as tranquilizers for decades and are mainly used to relieve anxiety. At the same time, their health hazards (addicted to addiction, etc.) are also well known. However, a study published last week pointed out the specific risk of combining them with opioid analgesics: When people taking opioids take benzodiazepines at the same time, the risk of overdose of opioids is five times higher.
doi:10.1001/jamanetworkopen.2018.0919
According to the National Institute for the Study of Drug Abuse at the National Institutes of Health in the United States, nearly one-third of the overdose of opioid drugs also involves benzodiazepines. This is because both drugs are inhibitors of the central nervous system. When they work together, they can cause dyspnea and lead to suffocation. Therefore, the FDA and other regulatory agencies repeatedly tried to emphasize the risks of these two drug prescriptions. In a forward-looking article published last month by the NEJM Journal, the FDA called for "proactive pharmacovigilance," which is to better track drugs prescribed by different or same doctors to patients.
DOI: 10.1056/NEJMp1806486
Only safer medications can be used as a long-term effective solution. At present, the development of non-addictive opioids has begun, and scientists aim to find compounds that have the same sedative effects but no dangerous side effects.
Found benzodiazepine related protein structure
On June 27th, published in the article titled “Structure of a human synaptic GABAA receptor” in Nature, the scientists proposed an advancement for this kind of research: they found a kind of mainly concentrated in the brain. Near the synapse, a detailed structure of the membrane protein called GABAA receptor. The physiological effects of benzodiazepines and other drugs are triggered by binding to this receptor.
https://doi.org/10.1038/s41586-018-0255-3
The authors describe that the structure of GABAA receptors is very complex and chemists cannot solve them using traditional structural biology techniques. As a result, they turned to cryo-electronic microscopy (cryo-EM), a technique that shoots electrons in a solution that is frozen in solution to solve more complex human protein structures. problem.
The GABAA receptor contains multiple subunits that can be arranged in so-called isoforms in various ways; this Nature paper focuses on the major subtypes found in human brain synapses. The high-resolution structure reveals how the neurotransmitters GABA (gamma-aminobutyric acid) and benzodiazepines bind to the interface between the subunits.
New alternative compounds?
The authors believe that the exact information on how benzodiazepines bind to this receptor can help develop new compounds that treat anxiety, epilepsy and other neurological diseases.
In addition, the complexity of the protein also helps explain one of its most significant features - versatility. In addition to binding to benzodiazepines, GABAA receptors can also be activated by compounds such as barbiturates, alcohols, narcotics and steroids. Therefore, understanding its structure also helps chemists find therapeutic compounds in these areas. Next, they will determine how these chemically different drugs work.
Finally, the researchers pointed out that traditional opioids and benzodiazepines have helped millions of people, and as long as they are used carefully, they will continue to benefit people. However, excessive use will inevitably lead to bad risks. Now, the involvement of infrastructure biology can point the way for us to use drugs correctly in the future.
