The University of Illinois at Chicago College of Pharmacy has received a $2.2 million federal grant to develop therapeutics to suppress the cravings of cocaine addicts.
Compounds developed by a research team led by Alan Kozikowski, professor of medicinal chemistry and pharmacognosy, will target one particular family of serotonin receptors in the brain. Recent evidence, he said, strongly suggests that these receptors, called 5-HT2 receptors, are important in controlling a person's desire to use drugs.
Researchers looking for therapies for cocaine addiction have largely overlooked the 5-HT2 receptor as a target, Kozikowski said, and focused on dopamine receptors instead.
"In large part, the field of cocaine medications research has been dominated by the so-called 'dopamine hypothesis,' where cocaine is known to block the re-uptake of the neurotransmitter dopamine.
"The higher levels of dopamine present in the cleft between neighboring neurons leads to cocaine's high," Kozikowski said. "This has led to years of work on the discovery of compounds that might displace cocaine from its binding site on the dopamine transporter, while still allowing dopamine to be taken up through the transporter.
"Success with this particular approach has been marginal at best."
The new target is a broad group of receptors that bind serotonin, also called 5-HT for its chemical name, 5-hydroxytryptamine. It is a neurotransmitter that controls a wide variety of behaviors, including anger, cognition, sleep, attention, sexuality and appetite. Low levels of serotonin may be associated with many health disorders, including clinical depression, obsessive-compulsive disorder, migraine headaches, irritable bowel syndrome and bipolar disorder.
The mode of action of 5-HT is complex, and at least seven different receptor 'families' are known, each located in various parts of the body and triggering different responses. Kozikowski's team is investigating the 5-HT2 family, of which there are three subtypes.
"The 5-HT2a and 5-HT2c receptors may play a role in the strong conditioned associations made between cocaine and environmental cues," Kozikowski said. Drugs highly specific for just those receptors will need to be developed, he said, because interactions with other members of the family can cause hallucinations and heart valve problems.
Kozikowski's collaborators -- a research team led by Dr. Bryan Roth of the University of North Carolina, Chapel Hill -- have identified an antidepressant drug as a possible lead candidate to identify other 5-HT2c-receptor-binding compounds that may be useful. This compound emerged after nearly 800 compounds in a chemical library were screened.
New 5-HT2c-receptor-binding compounds might be useful "both as research tools and as potential therapeutics for use in treating cocaine addiction and possibly other disorders, including obesity," Kozikowski said.
"We have already generated about 100 new [receptor-binding compounds] showing much higher potency and subtype selectivity than shown by the original 'hit' compound," Kozikowski said. "Further structure-activity studies are underway to fine-tune the compounds to a point where high activity is maintained at the 5-HT2c sub-type with little or no activity at the other subtypes."
Kozikowski said tests are currently being conducted in animal models at the University of Texas Medical Branch in Galveston by his collaborators Kenneth Johnson Jr. and Kathryn Cunningham.
The research is funded by a four-year grant from the National Institute on Drug Abuse, one of the National Institutes of Health.
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