Project Details


This grant application is the molecular pharmacology portion of an
Investigator Initiated Interactive Research Project designed to identify
pharmacotherapeutic agents that can be used in the treatment of cocaine
addiction. The strategy of this research initiative is three-fold.

I. Medicinal Chemistry: A panel of 50-75 novel benzamide derivatives of
2,3-dimethoxy-N-(p-flurobenzyl)piperdin-4-yl benzamide (MBP) and 2,3 -
dimethoxy-N-(9-p-flurobenzyl)-azabicyclo[3.3.1]nonan-3beta-yl benzarnide
(MABN), which are known to be high-affinity, nonselective antagonists for
D2 and D3 receptors, will be synthesized.

ll. Pharmacology: Genetically engineered eukayotic cells, expressing high
levels of D2-like dopamine (D2, D3 and D4) receptors, will be used to
characterize the pharmacologic selectivity of each benzamide derivative
for the three D2-like dopamine receptor subtypes.

Ill. Behavioral Studies: Those benzamide derivatives exhibiting the
greatest selectivity will be used 1) to determine their efficacy for
antagonizing the reinforcing effects of cocaine self-administration in
primates using behavioral paradigms, 2) to investigate the molecular
properties of the D2-like neurotransmitter binding sites using affinity
labeling techniques, and 3) to explore the potential for using receptor
subtype selective irreversible antagonists as a therapeutic tools for
drug abuse rehabilitation.

Although cocaine's reinforcing effects are known to be mediated through
dopamine neurotransmission, it is not clear which of the dopamine
receptor subtypes play a predominant role in reinforcement. One obstacle
to defining which dopamine receptor subtype(s) are involved in
reinforcing effects is the lack of high-affinity, selective antagonists
for each of the receptor subtypes. The experimental strategy for this
proposal is to 1) develop a genetically engineered recombinant
baculovirus virus that can be used to infect Sf9 cells for the expression
of D2, D3 and D4 receptors, 2) use radioligand binding techniques to
define the pharmacologic selectivity of a panel of novel benzamides for
D2, D3 and D4 receptors expressed in Sf9 cells, and 3) prepare and
characterize affinity labeling reagents that can be used a) in concert
with dopamine receptor subtypes expressed in Sf9 cells to determine the
position and orientation of benzamides within the neurotransmitter
binding sites of D2, D3 and D4 dopamine receptors, and b) to explore the
feasibility of using irreversible receptor blocking agents as a
therapeutic tool in the treatment in cocaine abuse.
Effective start/end date30/09/9431/08/95