RIMI Research: Synthesis of Novel Agents for Use - Synthesis of ...
Synthesis of Novel Agents for use
in Addiction Treatment
Dr. Karla-Sue C. Marriott ( Principal Investigator)
Funded by National Institute on Drug Abuse/National Institute of Health , R03DA027086 (April 2010-2012)
Preliminary Research Work was funded by RIMI- NIH (2009-2010)
• Drug addiction is a widespread problem of increasing concern
• Sharing injection drug works such as needles or syringes with
someone who is HIV positive is the second-most-common
way of contracting HIV among both black men and black
• Drug use and particularly methamphetamine use is on the
increase among African-Americans. This is often associated
with higher incidence of unprotected sex.
• Treating drug addiction is therefore a reasonable strategy for
fighting the transmission of HIV.
• A greater risk for the presentation of psychosis appears to be associated with the use of substances such
as cocaine, methamphetamine, cannabis and alcohol, as a substantial number of substance users
• Cocaine has a similar psychomotor stimulant effect to that of methamphetamine. It acts by increasing the
concentration of monoamine neurotransmitters (noradrenaline, serotonin and most importantly
dopamine) in both the noradrenergic and dopaminergic synapse. This occurs as a result of blockage of the
transporter protein responsible for monoamine reuptake. Like methamphetamine, it produces euphoria,
tachycardia, hypertension and appetite suppression. Cocaine has a strong reinforcing action, causing rapid
psychological dependence, an effect even more pronounced in those who smoke crack cocaine.
• Post-mortem studies of drug addicts indicate elevated levels of Dopamine D3 receptors in the mesolimbic
regions of the brain responsible for feelings of reward and pleasure.
• The density of D3, not D2 receptors was observed to be elevated in off-treatment psychotic patients.
• The concentration of dopamine D3 receptors is significantly greater than that of dopamine D2 receptors in
the mesolimbic regions supporting the idea that D3 receptors may be critical targets for effective
therapeutic intervention to assist in treating addiction.
• Medication to improve cognitive skills, reverse impairments, as well as address the resultant psychosis
experienced as a consequence of addiction to drugs is a priority for successful rehabilitation therapy.
• Our objective in this project is to determine dopamine D1, D2, D3, D4, D5
and serotonin 5-HT receptor affinities for novel benzofuro-benzazepine-6-
• We will also look at binding affinity at serotonin 5-HT receptors.
• Binding at the serotonin receptors, may provide the added benefit of a
reduction in the occurrence of extrapyramidal side effects such a tremors,
slurred speech, anxiety, paranoia, and involuntary muscle movement.
• In general, we expect to assist in the development of D3 receptor selective
antagonists or partial agonists for use as antipsychotics in the treatment of
addiction related psychosis. This we expect will assist in increasing the
success rate of individuals undergoing rehabilitation as well as reduce the
rate of relapse.
1. Refine a synthetic pathway for production of novel potential D3
receptor selective ligands as therapeutic agents. (Dr. Marriott,
2. Determine dopamine D1, D2, D3, D4, D5 and serotonin 5-HT
receptor affinities of each newly synthesized ligand. (Dr. Bryan Roth,
3. Perform functional assays on ligands exhibiting high to modest
affinity for the above receptors. The physiological effect of ligands
exhibiting selectivity and/or good affinity for dopamine receptors
D3 and/or D2 will be evaluated on DA clearance in the nucleus
accumbens of rats using voltammetry. (Dr. Tina Thompson, Mercer
University, Savannah Campus)
Benzazepine derivatives have been reported to possess anti-depressant properties
and are quite useful in the treatment of chronic neurological disorders including
brain damage resulting from epilepsy, stroke, Alzheimer’s disease, drug abuse and
• The proposed studies are relevant to the development of
dopamine D3 receptor selective medicinal agents for use in
the treatment of addiction. The results from this project will
contribute significantly to advancements in the area of
addiction research and rehabilitation treatment.
• Overall this research is expected to assist in promoting the
mental health of recovering addicts as well as reduce the
possibility of relapse.
• RIMI-NIH - initial funds
• NIDA-NIH – current funds
• Mercer University – Dr. Thompson (Collaborator)
• UNC-Chapel Hill- Dr. Bryan Roth (Pharmacology)
• Clemson University- Dr. John Huffman
• Savannah State University