Advances in 3-Phenyltropane Analogs: F. Ivy Carroll at Work

"A compound that provides some of the rewarding properties of cocaine—but not all of them"

In the 1990s, RTI teamed up with the National Institute on Drug Abuse (NIDA) to better understand the biochemical mechanisms of cocaine addiction. RTI chemist F. Ivy Carroll spearheaded this initiative, in collaboration with Michael Kuhar of NIDA's Addiction Research Center. Kuhar had identified brain receptors correlating with cocaine addiction, and he and Carroll teamed up to design and synthesize various compounds as potential pharmacotherapies.

Their research culminated in the development of RTI-336, a compound synthesized in 1993 and subsequently patented. "RTI-336 is an indirect dopamine agonist therapy, a compound that provides some of the rewarding properties of cocaine but not all of them," Carroll explains. "Part of cocaine's abuse potential is the rush people get due to a fast onset of action, but the effect crashes after about 30 minutes and leads to bingeing. RTI-336, which has a slower onset and longer duration of action, does not possess this attribute." Pre-clinical studies of RTI-336 in animals were successful, and the drug is currently being investigated for use in humans.

In further research, Carroll showed that another cocaine analogue, RTI-55, had tremendous potential as a diagnostic agent for people suffering from Parkinson's disease, a disorder of the nervous system that initially causes uncontrollable trembling and, in its late stages, interferes with muscle activity throughout the body and eventually causes death. This disease occurs when brain cells that produce an essential chemical messenger, dopamine, begin to die in large numbers.

"The only diagnostic technique for Parkinson's in the early 1990s was a clinical examination, and it was very difficult for physicians to determine whether the symptoms were in fact Parkinson's and not other types of central nervous system disorders," says Carroll. "The exam was not foolproof, and yet early detection is critical since you can slow Parkinson’s progress with preventive drugs."

RTI-55 changed the diagnostic picture by identifying the absence of dopamine-producing neurons in the brain, a condition suggestive of Parkinson's. When combined with a radioactive label, the compound binds to neurons that play a central role in regulating the amount of dopamine in key parts of the brain. Lack of these dopamine neurons, as seen on scans, is strong evidence that the patient has Parkinson's disease. Marketed as Dopascan and Iometopane, the diagnostic agent is in wide use around the world today, largely thanks to Carroll's tireless research in the 1990s.