Other than the poppy…
Pain, like death and taxes, is part of the human condition. Can’t escape it. So, it’s no surprise that humans figured out how to make drugs (from the opium poppy) for pain relief, centuries ago – and it’s been a valued commodity, ever since.
So explained Scripps Florida associate professor, Laura Bohn, Ph.D., as she embarked on her presentation, “Taking the Pain out of Drug Discovery,” at January’s Front Lines of Hope Discussion Series. Bohn investigates G protein-coupled receptors, which are critical to how patients respond to various drugs, including those used for the treatment of pain.
By 1805, she recounted, Wilhelm Adam Serturner isolated a component of opium and started pharmaceutical manufacturing. There are many derivatives: morphine, heroine, oxycodone, Percocet, and the synthetic, methadone. However, like all valuable assets, opiate narcotics do come with a price tag.
Its worse side effects are dependence, addiction and overdose, but there are others to contend with. Because, morphine, for example, affects the entire body. It offers sedation and euphoria; it induces an itching sensation, may cause respiratory failure, and, since it also affects the gut, constipation.
What if, asks Bohn, we could just turn on the receptors for pain relief, and turn off those other receptors?
The receptors are the targets where the drug acts on the cell. They traverse the cell membrane, she explained. So, when a person takes the drug, it’s able to get into the cell, change the cell’s shape and lead to the recruitment of proteins in the cell.
Bohn’s lab works on beta arrestins, a protein that determines how drugs act at the receptors, turning them on or off.
“To determine the effect, many years ago, we generated mice that lacked the protein of beta arrestin-2, and we gave them morphine. What we found is that we got the pain relief, but not tolerance, physical dependence, constipation and respiratory problems.
“So we know that we can have signaling for pain relief, in the brain, but in the gut, we can have it turned off for constipation.
“Over time, though, it gums up the works and you become tolerant to the drug. But it doesn’t happen in the gut. We believe that beta arrestin doesn’t work on that gear.
“So, what if we could make drugs that activate the receptor without recruiting beta arrestin-2?
“That’s the motivation of our drug discovery.
A component in one of the drug candidates was derived from Salvia Mexican Mint, and scientists made a drug that did that, but it is not good in solution, because it’s not stable, she said. “We just started a start up getting the compound ready for clinical trials.
“We can have pain relief without the side effect of constipation? Very soon, and without fear of addition or overdose,” she said.
Relating to the neurotransmitter serotonin, there are many good therapies (antidepressants) that have lousy side affects, she continued, showing an illustration of a neuron in the brain releasing serotonin. “In a normal state, we have enough to maintain a good mood, and it is taken up by the transporter.
“On the other side, the receptor is blocked and we get all those serotonins in the receptors.
“Why block serotonin uptake? Why not make something that targets the serotonin 2a receptor?”
If you make an agonist (a chemical that binds to a receptor, and triggers a response by that cell.), you end up with a hallucinogenic compound, like LSD, psilocybin, endogenous tryptamines.
And some of the serotonin metabolites can cause hallucination.
If you have too much serotonin, you have side affects, and as levels increase, you have hallucinations and ultimately coma and death from serotonin syndrome.
“So question is, can we refine serotonin therapies by fine-tuning serotonin receptors? We don’t want too much or too little. It’s got to be normal. Can we identify the gears that make up the machine that the serotonin receptor 2a responds to?
“Its very early, but we have found two signaling pathways,” she said.
Another new avenue in drug discovery is a compound derived from pinwheel jasmine. “When we tested it in mice, we found it was an analgesic. It’s not an opioid, and it doesn’t have any side effects. This may represent a new class of pain medications. We haven’t found a target for it yet.”
Written for Palm2Jupiter