Building a Safer Opioid from the Ground Up

Typically, the creation of a new drug is a process of tweaking or combining existing drugs to alter outcomes and side effects. A recent collaboration between researchers from Germany and across the United States, however, takes a novel approach in the battle against opiate addiction: trying to build a new painkiller from scratch.

"Morphine transformed medicine," according to Brian Shoichet, PhD, of the University of California San Francisco's School of Pharmacy, a co-author on a paper detailing the new project. "There are so many medical procedures we can do now because we know we can control the pain afterwards. But it's obviously dangerous too.”

The team set about trying to create a new breed of opioid that suppressed both its potential for addiction and the side effects that can turn that addiction fatal. The primary cause of death in an opiate overdose is usually respiratory depression.

To build from the ground up, Brian Kobilka, MD, of the Stanford University School of Medicine, modeled the atomic structure of the brain’s “morphine receptor.” That model, in combination with a computational simulation method developed in the 1980’s by UCSF’s Tack Kuntz, PhD, called “molecular docking,” allowed the team to simulate trillions of experiments.

The simulations sought to identify a chemical combination that could activate the morphine receptor while not stimulating the biological pathways associated with breathing function. All the while, the combination needed to avoid the brain’s dopamine circuitry in order to lessen the drug’s addictive nature.

After 4 trillion simulations, the team was left with 23 candidate molecules. Co-authors Dipendra Aryal, PhD, and Bryan Roth, MD, PhD, both of University of North Carolina, led the group in selecting the most potent one of the 23 candidates.

Joining forces with Peter Gmeiner, PhD at the Friedrich-Alexander University Erlangen-Nürnberg in Germany, the researchers then optimized the selection’s chemical efficacy. They named the concoction PZM21, and began testing it on mice.

The early returns from those tests are encouraging. In a related press release, PZM21 was observed “efficiently blocking pain without producing the constipation and breathing suppression typical of traditional opioids.” The mice also did not display “conditioned place preference”, a habitual behavior associated with addiction.

The researchers stress that they haven’t yet proven that the formulation is truly non-addictive, though the press release states that PZM21 is “chemically unrelated to existing opioid drugs.”