Research Interests
I am interested in neuropharmacology, the science of how drugs affect
neurons, and in psychopharmacology, the
science of how drugs affect consciousness.
These two disciplines are complementary, but neuropharmacology is the
broader field, because some drugs affect neurons but do not produce changes in
consciousness. My studies are focused on
those that do. Psychoactive drugs change
our moods, feelings, perceptions, memory, desires, and thinking itself. Because neural activity and consciousness are
somehow related, it is hoped that by understanding how psychoactive drugs
interact with neurons, a better understanding of how these drugs change
consciousness will emerge.
Research in my laboratory is focused on drugs
that act at neurotransmitter uptake transporters and receptors. The uptake transporters of interest are of
two major types: vesicle monoamine
transporters (VMATs) that package neurotransmitters into synaptic vesicles
for later release, and cell-surface
transporters that remove neurotransmitters from the synapse after they have
been released. Receptors are those
proteins upon which the neurotransmitters act to modify various neuronal
functions such as cellular biochemistry and firing rate. We are designing, synthesizing, and
evaluating new compounds that act at the transporters and receptors.
The transporters and receptors described
above are the sites of action of a many interesting psychoactive drugs. A sampling includes the antidepressants
fluoxetine and imipramine; the entactogen N-methyl-3,4-methylenedioxyamphetamine (MDMA); psychostimulants such
as cocaine and methcathinone; and psychedelic agents such as LSD, N,N-dimethyltryptamine
(DMT), mescaline, and psilocin. My
laboratory studies all of these compounds but recently we have been paying
closer attention to DMT. This is a
natural substance produced in the human body but it is psychedelic if ingested
in sufficient amounts.
Another area of interest is the family of
compounds known as aminoalkylarylones. Some examples of these compounds are the
psychostimulant methcathinone, the anorectic drug diethylpropion
(Tenuate®),
and the atypical antidepressant and smoking-cessation aid bupropion (Wellbutrin®,
Zyban®).
We have synthesized several new compounds with various structural modifications
to the aromatic ring and the alkylamine side-chain
and we are testing them for binding in
vitro and for behavioral activity in
vivo. Some of these compounds are
shown below.
Because of the aryl ketone function in the
chemical structure, these drugs are sensitive to light and they can be induced
to form covalent bonds within their receptor binding sites when they are
exposed to light. This makes them useful
for a molecular probing technique known as photoaffinity labeling, which is
used to identify and characterize drug binding sites.
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