My research interests involve the molecular neuropharmacology of psychoactive drugs. Currently, I am mostly
investigating drugs that act at the neuronal monoamine uptake transporters and
receptor sites. The transporters are cell-surface proteins that are responsible
for removing the neurotransmitters serotonin, dopamine, and norepinephrine from
the synaptic cleft following their release. Receptor sites are those proteins
upon which the neurotransmitters directly act to modify neuronal functions such
as firing rate, sensitivity to electrical and chemical signals, and so on. After
being taken up by the transporters, the interneuronal
signals are terminated and the neurotransmitters are repackaged into synaptic
vesicles for reuse. The monoamine uptake transporters and receptors are the
sites of action of a huge variety of psychoactive drugs. A small sampling includes the antidepressants
fluoxetine and imipramine
(serotonin transporter), the entactogen N-methyl-3,4-methylenedioxyamphetamine
(MDMA; serotonin and dopamine transporters), psychostimulants
such as cocaine and amphetamine (serotonin, dopamine, and norepinephrine
transporters), hallucinogens such as LSD, mescaline, and psilocybin (various
monoamine receptors), antipsychotics such as haloperidol
and olanzepine (dopamine and serotonin receptors),
and the anxiolytic buspirone
(serotonin receptors). In my laboratory, we are designing, synthesizing, and
evaluating new compounds as molecular probes for drug binding sites within the
monoamine transporters and receptors. Some of our new compounds are also being
evaluated as potential therapeutic agents for treating psychiatric diseases
associated with aberrant monoamine neurotransmission.
The present focus is on a family of compounds
known as aminopropiophenones. Some examples of aminopropiophenones 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 aminopropiophenones with various structural
modifications to the aromatic ring and the alkylamine side-chain and tested
them for binding in vitro and for
behavioral activity in vivo. A
receptor screen of some of these compounds against some 70 or so receptors, ion
channels, and transporters revealed that, in addition to binding at the
expected monoamine binding sites, there was significant binding to sigma-1
receptors. Experiments are underway to
further characterize this sigma-1 binding using pure receptor protein and we
are also testing additional novel aminopropiophenones for binding to this site. We hope to be able to locate the amphetamine
binding site within this receptor using the photoaffinity labeling approach
described below. Behaviorally, these
compounds act as antidepressants; in the Porsolt swim
test for antidepressant activity, some of the compounds are more potent than bupropion.
Because of the aryl ketone function in the
chemical structure, these drugs are photoactive and can be induced to form
covalent bonds within their binding sites upon exposure to light. This
technique is known as photoaffinity labeling.
Some of the new aminopropiophenones can be used as photoprobes to
identify and characterize binding sites for amphetamine-like drugs. A 60 kD protein from human platelets has
been labeled with a new radioiodinated photoaffinity probe based upon the
aminopropiophenone skeleton. The labeling is protectable by drugs such as fluoxetine,
MDMA, and methcathinone. We will also attempt to photolabel
the pure sigma-1 receptor as discussed earlier. [3H]- and [14C]-labeled derivatives of this drug have
also been synthesized for use in pharmacological studies.
I am also interested in the pharmacology and strucutre-activity relationships of hallucinogens such as ring-substituted phenylalkylamines, tryptamines, and lysergamides. These drugs produce a dream-like state with visual imagery, synesthesia, changes in emotional tone, and cognitive effects. It is emerging that these agents act as partial agonists at serotonin receptor subtypes, which suggests a role for serotonin receptors in these mental processes. I am developing a photoaffinity label for these receptors based upon the hallucinogen 2C-I; eventually we will try to identify amino acids within the 5-HT2A and 5-HT2C receptors that are derivitized by the new probes.
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