Challenges with social interactions, including face-to-face communication, can accompany depression, schizophrenia, and autism spectrum disorders. Doctors have long sought medication as a way to address these challenges, but no truly effective drug has yet been discovered. Some researchers think cell-signaling problems involving oxytocin—the peptide hormone responsible for social bonding, among other behaviors—might be a contributing factor. However, the therapeutic potential of oxytocin is difficult to study because it breaks down quickly in the body. In a new study, researchers have shown that two longer-lasting oxytocin analogs can affect social functioning for up to 24 h in mice genetically engineered to have autism- or depression-like characteristics (J. Med. Chem. 2019, DOI: 10.1021/acs.jmedchem.8b01691).
The researchers found that these new compounds bind quickly to oxytocin receptors and have long-lasting action, something that has not been found before with other oxytocin analogs, says study author Haruhiro Higashida, a neuropharmacologist at Kanazawa University. Building on previous work, Higashida, medicinal chemist Satoshi Shuto of Hokkaido University, and colleagues synthesized a series of six oxytocin analogs that had either N-(p-fluorobenzyl)glycine or N-(3-hydroxypropyl)glycine replacing a proline on the oxytocin backbone.
Then the researchers tested how tightly both oxytocin and the analogs bound to human oxytocin receptors from cultured human cells. The researchers found that one of their fluorobenzyl analogs acted as a superagonist in their oxytocin binding test, which means that it bound even more strongly to the receptors than oxytocin. It’s not unusual to get a chemical with bigger effects than the natural product, Higashida says. “In this case, we unexpectedly found one analog which showed 30% higher potency, which has not been reported before in the oxytocin analog field.”
To test the duration of the analogs, the researchers injected two of the most promising ones into mice that had a genetic mutation impairing oxytocin signaling and compared them with oxytocin. They then measured the mice’s performance on a number of tests designed to demonstrate nurturing or depression-like behavior. Higashida and coworkers found that the effect of oxytocin on social behavior disappeared in the engineered mice after about 6 h. But the two analogs remained active for up to 12 h, and one of those—the hydroxypropyl analog—was still affecting the mice’s behavior at 24 hours.
However, when they tested the mouse’s blood for levels of the compound after injection, the researchers found that the fluorobenzyl analog disappeared faster than oxytocin or the hydroxypropyl analog did. They could determine the presence of the hydroxypropyl analog after 30 m and 12 h but not its exact concentration because it was below the detection limit of the instrument.
Their results in the mouse models were stunning, says Kazimierz Wisniewski, a senior scientist at the Ferring Research Institute. However, not being able to measure the longest lasting analog in the mouse’s blood was disappointing, he says. “Yes, oxytocin does something, but unless we can demonstrate that it goes to the brain in some meaningful amount and explain why the compound works and is long acting,” it’s going to be difficult to move these compounds forward into more advanced testing, he says. “I don’t think the [compounds] described here are the ones we can use for treating people, but it’s a step in the right direction.”