Researchers  have  lately  discovered  a new  synthetic drug that emerges to nullify pain as effectively as morphine (Opioids) but without the side-effects that make Opioids so harmful and addictive.
Painkiller Tablet


Worldwide doctors use Opioids as a painkiller for treating any kind of pain to their patients. Opium and its derivatives have been used to dull pain (and generate euphoric feelings) for more than 4,000 years.Even in the era of modern medicine, morphine, derived from the opium poppy, has remained the painkiller of choice, whether for post-op recovery or on the battlefield.

Anyway doctors are looking for an efficient drug for reducing pain, as Opioids are not a safe drug and they make addictive people to it. So it’s become very necessary for the medical scientists to invent a new safe drug which will work as morphine(Opioid).


“But it is obviously dangerous too,” said Brian Shoichet, a professor at the University of California’s School of Pharmacy in San Francisco, and one of three senior authors of the study.

Again Opioids are among the most commonly prescribed painkillers in the United States, and they are also the deadliest; each day, 78 Americans die from an opioid overdose. Now,scientists have developed a safer form of the drug, which they say could reduce the number of overdoses and combat addiction. As a result people have been searching for a safer replacement for standard opioid for decades.

“Morphine transformed medicine,” says Brian Shoichet, a professor of pharmaceutical chemistry in UC San Francisco’s School of Pharmacy and co-senior author on the new paper in ‘Nature’. “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.

A recent study published in the journal ‘Nature’, researcher’s release how they deciphered the atomic structure of the "morphine receptor" in the brain to create a drug compound that blocks pain just as well as morphine, but without the harmful side effects that can lead to patient death.


Poppy flower. Morphine is derived from the opium poppy


The research represents a turning point in the way of scientists has traditionally tried to handle opiate addiction and overdoses.

For decades, they’ve attempted to tackle one addictive painkiller after another by coming up with an even stronger drug to treat the addiction to its parent.Morphine was designed to curb opium cravings, and both codeine and heroin were lauded as no addictive painkillers.

In lab tests, the new drug also appears to side-step the brain’s dopamine-driven addiction circuitry and does not cause drug-seeking behavior in mice.

Even though this hasn’t worked, some scientists in Japan announced earlier this year that they’d created yet another addictive opioid, this time of the GMO variety.

What is more, the research group says - unlike current Opioids - the compound does not activate the brain's reward region, so it has the potential to reduce addiction.

Common classes of Opioids include hydrocodone(Vicodin), oxycodone (OxyContin, Percocet) and morphine (Kadian, Avinza).

According to the Centers for Disease Control and Prevention (CDC) between 1999 to 2014, sales of prescription Opioids in the U.S. almost quadrupled. However, during the same period, there was no increase in the amount of pain reported by Americans.

Alongside the soar in opioid prescription sales come to a similar increase in prescription opioid deaths between 2000-2014, the drugs were responsible for almost half a million deaths in the U.S.

This has caused much concern among healthcare professionals,and earlier this year, the CDC issued new prescription guidelines to help tackle what has been referred to as the "opioid epidemic."


The virtual experiments that lead to novel opioid chemistry

Much of drug discovery, Shoichet says, begins by taking a successful drug like morphine and tweaking its structure to try to get rid of side effects while maintaining its primary function. The new study took a different, much more radical approach: "We didn't want to just optimize chemistry that already existed," Shoichet said. "We wanted to get new chemistry that would confer completely new biology."

An illustration shows PZM21


Much of drug discovery, Shoichet says, begins by taking a successful drug like morphine and tweaking its structure to try to get rid of side effects while maintaining its primary function. The new study took a different, much more radical approach: "We didn't want to just optimize chemistry that already existed," Shoichet said. "We wanted to get new chemistry that would confer completely new biology."

Keyto the new paper was knowing the atomic structure of the mu-opioid receptor,the brain's "morphine receptor," which was recently deciphered by co-senior author and 2012 Nobel laureate Brian Kobilka, MD, a professor of molecular and cellular physiology at the Stanford University School of Medicine.

"With traditional forms of drug discovery, you're locked into a little chemical box," Shoichet said. "But when you start with the structure of the receptor you want to target, you can throw all those constraints away. You're empowered to imagine all sorts of things that you couldn't even think about before."

With this structural information in hand, Shoichet's team turned to a computational approach called molecular docking, which was pioneered in the 1980s at UCSF'sSchool of Pharmacy by Shoichet's mentor, emeritus professor Tack Kuntz, PhD. Ina two-week period, the researchers performed roughly four trillion"virtual experiments" on a UCSF computer cluster, simulating how millions of different candidate drugs could turn and twist in millions of different angles to find those configurations that were most likely to fit into a pocket on the receptor and activate it. They also strove to avoid molecules that could stimulate beta-arrestin2, part of a biological pathway linked to the respiratory suppression and constipation typical of other Opioids.

This led to a short-list of 23 candidate molecules judged by the software and the research team -- especially co-lead authors Henry Lin, PhD of UCSF and Aashish Manglik, MD, PhD at Stanford -- to be most likely to activate the mu-opioid receptor in the way the researchers wanted.

Dr.Aashish Manglik of the Stanford University School of Medicine and Henry Lin of the University of California San Francisco (UCSF) “discovered” PZM21 by searching for a compound that would precisely fit a specific type of opioid receptor in the brain and spinal cord.

Using powerful computers, Manglik and Lin tested more than 3 million compounds, each in an average of 1.3 million configurations.

Manglik said: “We tried to look for molecules that would still bind to this 3-D structure, but are as far away from morphine and codeine as possible.”

The duo then manually checked the top 2,500compounds, selecting just 23 for further testing. Seven of them seemed especially promising. The researchers then tested 500 analogs of the 3 of them and narrowed down the field to 15, then 7, then finally 1.

Manglik and Lin tweaked that 1, final compound,rearranging the atoms in the molecule to get the best possible fit. The end result is the compound PZM21.

The new drug (PZM21) application on the lab mice

As the team gave PZM21 to mice in the lab, they found that the molecule was able to target the elected opioid receptor, relieving pain on the level of morphine.

Actually, the more PZM21 the mice were given, the more pain relief they experienced. The composite reduces 87% of the rodents’ pain,compared with 92% for morphine.

Amazingly, this was successful without triggering the constipation that the morphine is known for.

PZM21 did cause breathing problems similar to morphine, but the animals’ breathing improved before the painkilling properties wore off. With morphine, respiratory depression continues even after the pain returns.


New drug testing on mice


The researchers also discovered that PZM21mainly targeted opioid circuits in the brain to relieve pain, with negligible impact on the opioid receptors in the spinal column, an ability no other opioid can claim.

However the truly thrilling finding was that PZM21 did not stimulate the dopamine pathways in the brain, which the reward systems are known to fuel addiction. In other words, the mice were largely pain-free, but they didn’t get inflated.

Professor Manglik said, “If you give a mouse a drug that activates its reward pathways like cocaine, amphetamine or morphine,the mice just run around more. In this compound, we saw very little of that.”

Future of the newly invented Opioid PZM21

PZM21 still has many hurdles to overcome before showing up in pharmacies. It must be proven safe for humans, and effective in clinical trials, a process that typically takes up to ten years.

“This promising drug candidate was identified through an intensively cross-disciplinary, cross-continental combination of computer-based drug screening, medicinal chemistry, intuition, and extensive pre-clinical testing,”Kobilka says.

“If you took away any one of these collaborator sit simply wouldn’t have worked,” Shoichet adds. “Without Kobilka’s structure,our computation, Roth’s pharmacology, and Gmeiner’s ability to put an atom inexactly the place you want it, this never would have been possible.”

Future research will also need to determine whether mice or people develop a tolerance to the drug, causing it to lose its painkilling potency over time.


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