ichard Mailman has a new baby named Dave, a new company named DarPharma, Inc., and a dream so big he’s embarrassed to dream it.

The dream, after almost two decades of monomaniacal work, seems right on the verge of coming true. In this dream, millions of people with Parkinson’s disease or Alzheimer’s disease or schizophrenia or drug addiction or various other neurological afflictions take a pill that would help them lead a more normal life. And in this dream, the pills arrive in time to help Mailman’s friend and long-time research partner, Steve Wyrick, who retired from Carolina because he was diagnosed with Parkinson’s disease.

But Mailman, professor of psychiatry, pharmacology, and medicinal chemistry, doesn’t dare dwell on this dream when he talks to potential DarPharma investors. For the record, when Mailman thinks business, these days, his stated motive is making money, and plenty of it. He has learned the hard way, he says, that investors understand this motive better than, say, impassioned idealism or obsessive scientific quests.

But before there were any investors, before DarPharma was so much as a gleam in Richard Mailman’s eye, there was indeed a scientific quest. Starting in the late 1970s, Mailman and his lab, working with Wyrick and others, took an interest in certain receptors that triggered messages in the brain — receptors for dopamine. This in itself was nothing unusual. Researchers and drug companies all over the world were focused on dopamine, a neurochemical that influences a wide range of brain functions and plays a role in several neurological diseases.

Take Parkinson’s disease, for instance. Parkinson’s affects 1.5 million Americans, and it begins when large numbers of dopamine nerve cells in the brain die. "Because this is a dopamine-deficiency disease, it’s rational to think that if you could somehow replace the dopamine you could make people better," Mailman says. "The problem is that you can’t just give people dopamine, because it will never enter the brain. So people have tried to use strategies that mimic dopamine. The most effective therapy that’s used today is a drug called levodopa, which the brain coverts to dopamine."

Oliver Sacks’ 1973 book, Awakenings, which became the basis of a play and a movie, told the story of a Parkinson’s patient who took levodopa and made a miraculous but temporary recovery. Today, most scientists believe that dopamine nerve cells themselves are needed to convert levodopa to dopamine. Because levodopa does not actually cure Parkinson’s, nerve cells continue to die. When there aren’t enough nerve cells to make the conversion, levodopa no longer works. Bill Snider, director of Carolina’s neuroscience center, has hired a group of researchers who are studying the process of brain-cell degeneration and how to prevent it, and others are studying how to repair the damaged brain. But for now, there is no cure or prevention for Parkinson’s disease — only the need for longer-lasting treatments.

Find the Right Mimic

The dramatic effects of levodopa, usually sold in combination with another drug under the trade name Sinemet, affirmed the importance of activating the dopamine receptors. Mailman and others wondered if the right receptors could be engaged without having to rely on dwindling numbers of nerve cells to produce the dopamine. What was needed, he thought, was a drug that would act directly on the critical dopamine receptors just as dopamine does. Trouble was, these receptors belonged to two different families — D1 and D2. The D2 family had gotten most of the attention because common wisdom was that they influenced the widest number of neurological functions. But Mailman wasn’t convinced that D2 was the answer, especially for Parkinson’s disease.

By the mid-1980s, Mailman and his research partner, Dave Nichols at Purdue, had evidence and a strong belief that the less-studied D1 family of receptors offered much greater promise. "No one agreed with us," Mailman recalls, "mainly because people had misinterpreted some of the data available then, but also because what we were doing didn’t fit the established models."

The limited number of signaling pathways activated by the D1 family of receptors seemed to Mailman as much an advantage as a limitation. D1 receptors affected such things as movement, thought, memory, and addiction, but they did not seem to cause behavioral disturbances or interfere with pain thresholds, the cardiovascular system, or other vital functions. To Mailman and his colleagues, this meant that drugs targeting the D1 family were less likely to produce dangerous or unwanted side effects.

So Mailman set himself squarely at odds with conventional wisdom and pursued D1 with a vengeance. "It was one of those intuitive kinds of things," he says. "I just couldn’t leave it alone, so I focused everything on this one direction. In retrospect, it was high risk, but it also seemed right."

He and Nichols looked for a "full agonist" — a compound that could bind to the D1 receptor and mimic the action of dopamine. Nichols was deft at designing new drugs, so he was a natural complement to Carolina’s basic studies of cell receptors and signaling pathways — studies being conducted in Mailman’s lab as well as in the lab of Alex Tropsha, associate professor in the School of Pharmacy. By the late 1980s, the team had synthesized the first full D1 agonist, a drug they called dihydrexidine. And they were ready to see if it worked.