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WAY-267464: The Love and Connection Drug?

Jett asked me about WAY-267,464, after finding this Wikipedia entry on it. After looking through my archives, I found that I had discussed this potential drug that Wyeth is working on with Dr. Robert Ring, Head of Molecular Neurobiology, Depression & Anxiety Disorders, Discovery Neuroscience, Wyeth Research.

The original draft of my book, The Chemistry of Connection, contained a whole chapter about potential oxytocin therapies. Unfortunately, my publisher didn't want much of this in the book. But there's immense interest in oxytocin drugs, and I believe that oxytocin is going to be the wonder drug of this decade -- or maybe next decade.

In February 2007, I interviewed Wyeth's Robert Ring about the potential for oxytocin therapies. Below is the section of the chapter discussing WAY 267,464, with some additional comments.

The delivery method -- how to get a drug inside someone -- is a huge issue for oxytocin. The nasal spray stings and doesn't last very long; injections hurt; IVs are cumbersome and unpleasant; pills break down in the digestive system before they have a chance to work.

That's why pharmaceutical companies will likely produce drugs containing proprietary oxytocin-like molecules, instead of bio-identical oxytocin. These designer molecules will bind with oxytocin receptors, but they'll have other characteristics that make them more effective or limit what they do.

Robert Ring, head of molecular neurobiology, depression and anxiety disorders, discovery neuroscience for drug giant Wyeth Pharmaceuticals, is unusual among drug company executives for being willing to discuss oxytocin drug development.

"We're blown away at the various diverse range of functions oxytocin seems to be acting on," he says. "Working at a drug company, you can't ignore the fact that oxytocin seems to be a multifunctional anti-stress peptide -- and it seems to be a potent analgesic as well."

One hot prospect is Wyeth's WAY 267,464. It's not a peptide like oxytocin is, which means that it won't degrade into other neurologically active substances. Instead, it's an oxytocin agonist, that is, it increases the effects of oxytocin. The advantage of treating with an agonist instead of simply trying to supplement the brain's natural supply is that often, when docs dose someone with a hormone, it further inhibits the body from producing it. WAY 267,464 also is less likely to cross over and bind to vasopressin receptors. This is important because, while scientists haven't nailed down vasopressin's role in human bonding and social interaction, it definitely seems to be important. So, the less you get in there and muck with unknown systems, the better.

In animal studies, the substance, known as 464, behaves much like oxytocin in reducing anxiety, and it also has some promise as an anti-psychotic.

Eric Hollander of the The Seaver Center for Autism Research and Treatment, Mount Sinai Medical Center, would seem to have a patent lock on teating symptoms of autism spectrum disorder, or ASD, and other disorders using oxytocin. Wyeth isn't concerned about Hollander's patents; it hopes to develop a unique molecule that binds to oxytocin receptors but has better properties for a drug. Neither is it working on an autism drug -- at least, Ring wouldn't say it is.

He pointed out that, although there's intense interest in using oxytocin to treat ASD symptoms. Because oxytocin and oxytocin-like drugs are a novel category, the path to FDA approval isn't clear. It might not be easy to demonstrate positive outcomes using standard methodologies.

Oxytocin's broad reach, relieving pain, reducing stress and soothing anxiety, could be an extra benefit for conditions with complex pathologies. Depression, for example, may go along with anxiety, chronic pain or physical illness. Oxytocin could potentially relieve these "co-morbid" conditions, Ring says. Easing any one of them would be important. Anxiety itself, he adds, is "a huge market."

Another promising area for the industry might be an antidepressant without the sexual side effects of selective serotonin-reuptake inhibitors like Prozac and Paxil. Over time, as these drugs increase the level of serotonin in the brain, prolactin also rises. Among its many roles in the body, prolactin induces the feeling of sexual satiety after orgasm. Chronically high levels of prolactin therefore can make you feel you've had enough sex, even if you aren't having any at all. An apathetic sex life is a common complaint among people on SSRIs.

Although oxytocin release is often promoted by serotonin, oxytocin also helps regulate sexuality, and it seems to be involved in erections of the penis and, presumably, the clitoris. So, it's possible that an oxytocin-based antidepressant could actually improve someone's sex life, as well as his frame of mind. Dr. Ring told me, "It's one thing to treat male erectile dysfunction, but there's a much bigger market for therapeutics for female dysfunction." While lubrication or engorgement problems may be neurological, oxytocin might be important for the motivational side of things. For example, if some aspect of sexual dysfunction had to do with anxiety about interacting with your partner, anything that would lower that anxiety might help.

(My editorial comment: For most women, anxiety about potential sexual partners is protective and a good thing. Ideally, any of these potential drugs would only be given to women with anxiety disorders. We hope.)

But don't expect 464 to turn into a pharmacological silver bullet. While its action in the body is remarkably like oxytocin's, Ring cautioned that this molecule may lack some of the properties of a good medicine. A successful oxytocin mimic should be able to be taken orally, and ideally, just once a day.

Wyeth Research is, of course, focusing on developing drugs to treat psychiatric disorders. But if a drug like this comes out, it may, like SSRIs or Provigil, also be taken up by people who haven't been diagnosed with a disorder but are just hoping to warm up their lives a bit.

This July 2009 paper in Neuropharmacology details tests of WAY-267464 on mice.

Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin agonist. 

And here is the Wyeth patent application for using oxytocin receptor agonists to treat schizophrenia and anxiety disorders.