The Promise of a Non-addictive Opioid

As far back as the late 1800s heroin was once hailed with the promise of being an abuse-free opiate. Although dozens of other opiates have been created, no one in the past 12o years has succeeded in creating a side-effect-free and non-addictive opioid. But by using a new approach, there is a chance that a German team led  by the anesthesiology and professor Dr. Christoph Stein has succeeded. Before delving into the specifics and exploring the chemistry, let’s provide some background information.

What Are Opioids?

An opioid can be any of these compounds: (1) it can be part of the group of substances directly made by, or derived from, the opium poppy; (2) it can be one of the human-brain-produced peptides that influence a variety of  behaviours including attachment, stress, food-intake and pain response; or (3) it can be a synthetic substance that binds to the same receptors as the previous two types. The receptors known so far include μ (mu—the m coming from “morphine”), δ (delta) and κ (kappa).

Opioids are used to treat pain brought on by terminal or serious illnesses, such as cancer. Some medical practitioners also turn to opioids for chronic pain, common among those with forms of arthritis, back injuries, torn muscles, damaged nerves and fibromyalgia. A case of kidneys stones, nature’s way of making men experience something almost as painful as childbirth, sure made me appreciate a dose of morphine. Since that experience, I have not needed a strong opiate.

Others are not as lucky and need more intense compound-assisted pain management, especially if other opioids have become ineffective. Fentanyl (trade names: Actiq®, Duragesic®, and Sublimaze®) is a quick-acting synthetic opioid with 50-100 times the strength of morphine. But transdermal patches of fentanyl are prescribed only when at least a week of tolerance towards opiates has already been established. That’s because with all its delivery-forms, the use of fentanyl can be very risky. Opioid receptors are all over the body, brain included, and fentanly will not only cause dopamine levels to spike, but it could also bind to brain receptors that control the breathing rate. Respiratory depression can be fatal, and the online availability of illicit fentanyl sold through decoy packages has led to an epidemic rise in fentanyl-related deaths in Canada, Estonia and the United States.

The first pouch on the right hides a few grains of fentanyl (enough to kill). The package was mailed from China pretending to be a set of urine-testing strips. From the Globe and Mail

Other undesirable reactions from binding to μ receptors include reduced gastrointestinal nausea, vomiting, and the accompanied euphoria from the ensuing dopamine-spike, which ties into addiction.

How A Safer Alternative Was Found

The researchers started by focusing on the role of MOR (μ opiate receptors) in injured tissues as opposed to the brain. They did this for two reasons (1) Painful conditions such as inflammation or trauma are often associated with a lower pH(acidification) in localized tissue. (2) Only the protonated form of opiates like fentanyl can bond to MOR receptors. To be protonated simply means that an H+ ion has been attached to a basic group, in this case the nitrogen of a heterocyclic ring called piperidine . Then through hydrogen bonding, that proton attracts the oxygen of a carboxylate group of an aspartic acid molecule on the receptor.

The protonated fentanyl shown bonded to an aspartic acid residue (Asp 147) of a μ opiate receptor. Modified from author’s paper in Science.

Fentanyl and other opiates have substantial fractions of their molecules protonated at pHs of about 5 to 7, where the source of pain lies.  But the problem is that opiates are also highly protonated at pH 7.4 , the typical pH of the brain and small intestines where you don’t want the opiates to be activated.

We will represent the protonated form of fentanyl as HNFen+ and the uncharged basic counterpart as NFen:

HNFen+ = H+ + NFen

What the researchers aimed to do was to attach a fluorine group to key positions of the fentanyl molecule to increase its acidity without altering the stereochemistry or functional groups of the rest of the molecule. After some computer modelling they suggested the synthesis of NFEPP:

The protonated form of NFEPP, which has been shown to be a non addictive opioid still capable of acting as an analgesic. This form becomes less important above a pH equal to its pKa of 6.8
The protonated form of fentanyl found in the commercial citrate. It’s also the predominant form below pH = pKa = 8.4, so in other words in any human tissue containing opioid receptors.

Even at the beta position (on the second adjacent carbon attached to nitrogen), fluorine’s electron-withdrawing presence decreases a nitrogen’s ability  to reattach itself to H+. This happens because nitrogen uses its electron pair to act as a base and bond to H+. If the reverse reaction is less likely to proceed, the acidic forward reaction is favoured. That is a good thing for the drug designers because they did not want the protonated form to dominate in certain tissues where it could lead to addiction and respiratory arrest.

To understand why a more acidic molecule will be adequately protonated in the proton-rich environment —where the pain is—and why there will be far less protonated than fentanyl at pH=7.4, let’s explore some analytical chemistry.

For weak acid systems like

HNFen+ = H+ + NFen , we cannot make the assumption that the H+ concentration will equal that of NFen. To estimate the relative concentration of the protonated fentanyl  we have to rely on the mass balance approach where we compare HNFen+ ‘s concentration, [HNFen+ ], to that of the total of  non H+ species.

We let X = [HNFen+ ]+ [NFen] = sum of concentration of non-H+ species.

so [NFen] = X – [HNFen+ ]

since its acid dissociation constant, Ka = [H+][NFen]/[HNFen+ ], by susbtituting for [NFen] we obtain:

Ka = [H+](X – [HNFen+] )/[HNFen+].  By then solving for [HNFen+ ], we obtain:

[HNFen+] =  [H+]X / ( Ka + [H+] )

Finally by rearranging the expression, we get the fraction of protonated species as:

[HNFen+]/X = [H+]/ (Ka + [H+] )

The expression suggests that the fraction of the protonated species is pH-dependent and is inversely proportional to the strength of the acid (measured by its Ka). If [H+] = Ka or if pKa = pH , we will get a mole fraction of exactly of 0.5. This implies that since NFEPP’s pKa is lower (6.8) than fentanyl’s, then the concentration of the protonated form will be the minority-species at a pH that’s lower than the crossover point for fentanyl. The latter has a lower Ka and hence higher pKa of 8.4. To better reveal the relationship, I plotted the fraction [HNFen+]/X versus the pH for both fentanyl and for NFEPP, which due to its fluorine has a higher Ka.

Notice how the fraction of the protonated form of NFEPP drops dramatically to about 10% at pH= 7.4 whereas that of fentanyl is still above 90%. Meanwhile NFEPP still acts as an analgesic because at pHs of 6.8 to 5.2, the fraction of the protonated form that’s needed to bond to μ receptors in inflammation areas is in the 52 to 95% range, respectively.

But does all this theory work in a biological environment? In the authors’ experiments, NFEPP produced analgesia in rats who had different types of inflammatory pain. And equally important the pain relief was not accompanied by typical opiate side effects such as sedation, decreased breathing, constipation or the desire to seek more pain-killer. In 4 to 5 years, the time it will take to refine the synthesis and test the product in humans, it will be interesting to see if the usual unforeseen consequences will be minor. Of course NFEPP ‘s inability to produce euphoria will not displace dangerous opiates from the black market. But it will help alleviate the problem by putting nonaddictive drugs into circulation while hopefully making the legitimate production and prescription of fentanyl and other opiates obsolete.


A nontoxic pain killer designed by modeling of pathological receptor conformations

Fluorine in Medicinal Chemistry ChemBioChem 2004, 5, 637 ± 643

Click to access BBD-Opioids-Full.pdf

A brief history of opiates, opioid peptides, and opioid receptors Michael J. Brownstein Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, MD 20892

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