The day dawns bright in Boston as the milling scientists at the Chemistry and Pharmacology of Drugs of Abuse conference finish their breakfasts and refill their coffees before the opening plenary by Alexandros Makriyannis. He's a giant in the field of synthetic cannabinoids and here at Northeastern University he invited pharmacologists, medicinal chemists and others of those biochemical stripes here to share data and insights about their individual fields of focus. Using their wide-ranging tools, the researchers here zoom intensely down into the drug of their expertise.
"I think morphine is the most beautiful molecule in the world—sorry to the people into cannabinoids or bath salts," begins John Traynor, a British pharmacologist now at the University of Michigan, setting the tone. With cheek, he continues about how only the old people will remember that “we used to build handmade molecules with glue and such."
But those clunky wooden models let those scientists view the infamous alkaloid's structure as a seductive series of rings and visualize their targets in the pharmacological hunt. They search through the molecules, the animals, the plants and the computers for the holy grail of pain relief—a more nuanced molecule that might do the job better, with fewer side effects, less addictive potential and less pharmacological harm from these often blunt but beautiful tools.
The search for new drugs and a better understanding of familiar ones can take many paths, and the scientists and researchers gathered in Boston are on the cutting edge. Thanks to this conference, sponsored by the federally funded National Institute for Drug Abuse (NIDA), we can catch a glimpse of what they're looking for and finding out. Our tour will take us through the plants, animals, receptors, and computer programs used by these researchers looking at the chemistry and pharmacology of drugs of abuse—and the drugs to treat addiction to drugs of abuse.
Of course, Traynor's advocacy of morphine as the most study-worthy molecule doesn't go unchallenged. Thomas Prisizano, the chief of Shaman Tom's Voodoo Science Lab, joyfully nominates salvinorin A (SVA) as his favorite molecule, a drug from the neoclerodanes, the class of chemicals behind the fabled effects of the salvia plant.
This research got its nickname after a mentor told Prisinzano that the study of plant compounds is a voodoo science—which is quite true. The complexities of plant chemistry still overwhelm us but while the mysteries of chemogenesis still usually lie beyond our grasp, they remain a major source of new drugs and pharmaceuticals.
Dr. Prisinzano shows slides of isolating the active ingredient, a process that begins with five kilograms of raw plant material and ends with less than an ounce of salvinorin A. This is a particularly messy activity compared to the work of many of these scientists, who tend to use reagents from chemical manufacturers instead of raw plants.
The scientists listen attentively to Prisinzano's pitch about why the SVA molecule excites so much interest. It acts on the kappa opioid receptor for pain and it's the only drug to hit that receptor that doesn't derive from the morphine molecule, with all its obvious drawbacks of addiction and tolerance. With his description of the salvinorin A as “exquisitely selective for kappa,” reversible by naloxone and much less addictive according to relapse studies in mice and self-administration in monkeys, it stands ripe as a candidate for one of the hallowed blockbusters sought by academics and pharmaceutical companies: a non-addictive alternative to morphine and its synthetic analog sisters.
SVA and many of its analogs possess one of the most unique psychoactive profiles of any drug, which includes the ability to change interoceptions—the senses stimulated from within the body—and even more rare, to alter one's psychological ownership of the body, leading to the strange phenomenon of the perception of one's body actually blending into the objects around one.
Of course, most researchers see these fascinating side effects as unwanted. Their goal is to separate the psychoactivity from the intended medical effect and fashion a drug more palatable to the FDA. Salvia provides a particularly rich array of synthetic options for tinkering with this molecule but there are many others, and the design of the molecule is only the first step. The trickiness only increases when testing the new compounds in animal models.
The Lab Animals
Continuing the molecular challenge, Scott Rawls of Temple University gave a shout-out to mephedrone. Known on the street as bath salts, this synthetic cathinone derived from the khat plant took the club scene by storm over the last few years and was the subject of particularly shoddy reporting around the so-called Miami cannibal (who had nothing in his system but cannabis and a history of psychosis). Rawls is investigating mephedrone because the animal data shows it possesses a marked ability to reduce the anxiety and depression from a cocaine withdrawal.
But how do the researchers test for such mental health effects in lab rodents? And does this data translate to humans?
To measure the “preclinical efficacy against stimulant withdrawal,” researchers use the Elevated Plus Maze, a platform raised off the ground in the shape of a plus sign with two of the arms enclosed and the other two open. It's a research method using a rodent's natural fear of open spaces to measure anxiety. The more time spent in the uncovered areas translates to less anxiety. For instance, give a mouse a Valium and it spends more time frolicking in the open air.
In Rawls' lab, grad students get mice hooked on cocaine or MDPV, another cathinone-type stimulant, by giving it to them three times a day for 10 days straight. Then for the next two days, the control group goes cold turkey while the experimental group receives the mephedrone twice a day. On the 13th day, the mice take the Elevated Plus Maze test. Lo and behold, the animals on drugs spent more time in the light.
Then, to test efficacy against depressive behavior, there's the forced swim test, or the "behavioral despair test." Here the mouse is placed in an inescapable transparent tank filled with water. The research protocol assumes that a happy mouse is one that keeps swimming, so the more time the mouse spends immobile and floating, the more depressed it is considered to be.
“Bloody hell! If you explain all this to a British club kid, they'd roll their eyes," one young researcher in the audience muttered. "Of course if you give a mouse bath salts it will have more pep in its step. Why, if you gave me enough, I'd swim across that Charles River and run naked across Harvard Yard too.”
The researcher went on to express no small amount of frustration over the notion of using new drugs to treat old drugs of abuse, saying it all reminded him of when they introduced heroin to treat morphine addiction.
And then there's the question of how to accurately measure higher-level emotional states in any lab animals lower than primates. It's a question that the researchers designing new molecules and trying to decipher their effects haven't resolved, and with the huge number of molecules to be tested and the tremendous expense of even the most basic Phase 1 clinical safety trials in humans, the gap looms large.
Charles Perry of the Center for Drug Discovery attacks the drug abuse problem from the opposite flank by looking for targets that might block the effects from a drug of abuse. Perry focused on a specific serotonin receptor, 5HT1A/7, a regulator of the dopamine, GABA and glutamate neurotransmitter systems, that's been associated with "compulsive novelty seeking behaviors." No drug approved so far specifically targets that receptor, but preclinical work with primates has seen it block ketamine psychoactivity.
Perry synthesized a drug to target that receptor, and it turned out to be a partial agonist. Partial agonists are seen as a pharmacological "sweet spot" because they can prevent the development of tolerance and lessens the danger of overstimulation that can lead to effects like the serotonin syndrome that so often strikes ravers who mix the wrong molecules. (Partiers, never ever ever mix MDMA & MAIOs. It absolutely can kill you and at least, it most certainly will wreck your night.) Perry hopes to block the psychoactive effects of drugs of abuse such as hallucinogens, amphetamines and dissociative anesthetics.
So how to measure how high your rodent is? For psychedelics, by counting the number of times the rat's head bobs. That's the DOI method, a creation of Alexander Shulgin, the intellectual father of a generation of psychonauts. The method records the occurrence of a characteristic rodent neck twist during the psychedelic experience, and Perry's new drug decreased the frequency of the bobbing, suggesting that it has blocking effects.
For dissociative drugs, the researchers don't mess around with ketamine, MXE, or even PCP, but instead go for the much more potent MLK 1. The physical criterion they measure is a psychomotor effect of repetitive rotation, which seems an odd measure of effectiveness because in humans, high doses of dissociatives usually result in someone puddled in the corner. For amphetamines, researchers look for hyper-locomotion, a characteristic high movement. Unfortunately for Perry, the partial serotonin agonists are unable to “significantly attenuate hyper-locomotion.”
All of this research begs the question: Why do we need to block the effects of these enjoyable drugs? It's not a question much reflected on by at this conference, sponsored by NIDA, whose charter written by Joe Biden limits it to looking only at the abuse of drugs and not examining their potential benefits. These drugs are labeled by the federal government as drugs of abuse and thus pharmaceutical counter-tactics are needed.
The researchers themselves tend to function as strict reductionists, often remaining within their narrow yet deep "silos." If a chemist and a biologist sat next to each other on a plane, they would likely run out of things to talk about rather quickly. One is zooming in on the trees while the other is trying to fly over the forest. Their worlds don't overlap. The isolating specialization exists in both fields, and in pharmacology, too, which already runs to a half dozen sub-specialties such as pharmacogenomics, neuropharmacology, posology and even theoretical pharmacology. For an example of the latter, we turn to Seva Katrich.
Of all the researchers mentioned, Dr. Katrich, a Moscow-born biophysicist, produces the publications probably most indecipherable to a layperson. To study important biological phenomena like the shape of DNA or the binding of receptors, he employs many tools, but today he came to share with his fellow researchers on the power of working in silico.
He begins by describing the G-Protein Coupled Receptor revolution. The GPCRs are a super family containing over 800 different human receptors. They share the same basic structure of a protein crossing the membrane seven times but otherwise display a diverse array of features. They occupy such an important space in the body that almost half of all approved pharmaceuticals in the United States target them. But visualizing these receptors remain a huge technical problem. If you can get a crystal structure for one, it's enough to earn you a paper in Nature, the scientific equivalent of a grand slam.
Katrich demonstrated the power of computation using the LIBERO (Ligand Guided Backbone Ensemble Receptor Optimization) algorithm. The program functions as a fast and reliable molecular modeling platform that improves the accuracy and reliability of receptor docking. If you're looking for a new drug by mucking about in the test tube or watching a few dozen mice to see if they're scared of their shadow, that's the old way. Now you use 4d modeling technology to generate multiple conformations to look for that magic word: druggable.
For this work, he turned his attention to the kappa opioid receptor as the therapeutic target (an obvious and wise choice because everyone wants to replace morphine for painkilling). In the computer, he generated 5 million chemical leads. Two hundred tested well as potential candidates. Forty-three looked like strong enough candidates to order synthesized by a chemical company. Twenty-seven of them worked well. Fourteen of them worked great. By the end, they generated six intriguing novel chemotypes to act as ligands on the kappa opioid receptor. Now they hope at least one will win its way through that narrow valley of human trials and onto the summit of FDA approval. This is drug discovery at the cutting edge. But is it a quixotic quest?
As the conference packed up after the closing speeches, a scientist old enough to have his own lab but young enough to still request anonymity shared his thoughts. He enjoys these conferences with their camaraderie of the chemical hunt, but he's growing jaded.
“The problem is that I've been coming here for five years and hearing the same thing," he says. "There's always a crop of new morphine analogs hoping to be the next non-addictive painkiller, but nothing ever appears. None of them actually ever get into human use.”
Every chemist aches to hit the jackpot and get a drug through the narrow straits of the FDA approval process, but the chances of that resembles an author writing a bestselling book or a musician hitting the top of the pop charts. There is nothing like that original morphine molecule and sometimes it seems there's little more that we can do but tinker with what nature hath wrought.