Created an opioid with no side effects

Oleg Lischuk, N+1

An international team of scientists has synthesized a low-molecular-weight opioid that does not have the serious side effects characteristic of this class of drugs. The results of the work are published in the journal Nature (Manglik et al., Structure-based discovery of opioid analgesics with reduced side effects).

Stimulation of mu-opioid receptors responsible for analgesia and euphoria, as well as the formation of dependence and depression of the respiratory center, can lead to the activation of two intracellular signaling pathways: G-protein-bound and beta-arrestin. Available opioids act on both of these pathways. The data accumulated to date indicate that the desired analgesic effect is realized through G-protein, and undesirable side effects are realized through beta-arrestin.

Morphine activation of the mu-opioid receptor
(here and below are the drawings from the article in Nature)

In search of a selective compound, Stanford University and other American and German research centers conducted computer screening of more than three million molecules for compliance with the three-dimensional structure of opioid receptors. At the same time, each of them was estimated at about 1.3 million configurations. 2500 of the best compounds were then analyzed manually for interaction with key polar sites (interaction sites) the active center of the receptor. Of the 23 molecules selected, seven demonstrated the greatest affinity for the mu receptor.

The strongest and most selective of them was then subjected to various chemical modifications in search of a substance with the best properties. 

The resulting compound with the working name PZM21 turned out to be highly selective against mu-opioid receptors, powerfully activated the signaling pathway associated with G-protein, and minimally affected beta-arrestin. It also had a minimal effect on the reflex pathways of the spinal cord, activating mainly the central mechanisms of pain suppression. 

In an experiment on mice, PZM21 in morphine-equivalent analgesic doses did not cause the animals to re-take, significant respiratory depression (the main cause of death in opioid overdose) and constipation. The maximum analgesic effect of the substance lasted up to 180 minutes, which is longer than when morphine was administered.

PZM21 can become a valuable alternative to the opioids used, but for its use in humans, as in the case of other drugs, large-scale preclinical and clinical trials are needed. The researchers also note that it will find application in research on the functioning of opioid receptors.

Interaction of PZM21 with the active center of the mu receptor

In early 2016, pharmacologists from Tulane University in New Orleans also reported the creation of four opioids without major side effects. They are peptides capable of penetrating into the brain, and are obtained by modification of natural neurotransmitters endomorphins. According to the researchers, the small severity of side effects is due to the fact that, unlike morphine, they do not act on neuroglia receptors (auxiliary cells of the nervous system).

Opioids are currently non-alternative painkillers in terms of effectiveness, which are most widely used in oncology and surgery. However, their use is limited by the side effects listed above. In addition, the laws of some countries (including Russia) related to the abuse of opioids dramatically reduce their availability to patients.

Portal "Eternal youth" http://vechnayamolodost.ru  29.08.2016