Team Dopamine Project Goals
The foci of this collaborative research will include:
- Based on existing structural leads, develop novel drugs having high
affinity and selectivity for D3 and/or D4 receptors, and characterize the
receptor interactions and functional effects of these drugs in molecular
expression systems and rat brain.
- Characterize novel Di-like ligands for utility as antiparkinsonian
and potential antischizophrenic drugs.
- Focusing on the D2 molecular isoform, determine the mechanisms for,
and implications of the isoform functional selectivity seen with tetrahydrobenzo[a]phenanthridines
and other compounds. This will involve in vitro and in vivo studies using
mammalian preparations, and later, examining these drugs in systems expressing
only one molecular form of this class of receptors.
- Establish reliable in vitro mesencephalic dopaminergic neuronal preparations
for single cell electrophysiology, and characterize drug effects in acutely
dissociated striatal, nigral, and nucleus accumbens neurons. Compare with
cultured cells expressing cloned D2, D3, and D4 receptors
- Model "D2-like" dopamine and muscarinic cholinergic receptors
and determine structural elements that affect ligand binding, and conformation
changes that determine the nature of interactions with different G-proteins.
- Develop and study models of neurotoxic insult to dopamine systems to
understand the adaptive responses to neural injury at both the functional
and molecular levels. These models would include partial striatal dopaminergic
lesions, serving as a model of early Parkinson's disease to study disease
effects on dopamine uptake and release. Other aspects of this work would
compare dopamine release in anesthetized (previous work) and freely moving
animals with an emphasis on effects on dopamine transporters and presynaptic
inhibitory D2 receptors, and would also determine how key mechanisms (e.g.,
D1/D2 receptor interactions) are changed in such models. These data will
be important in understanding and developing new therapies for Parkinson's
disease and schizophrenia.
- To compare and contrast the effects on dopaminergic transmission of
chronic administration of clozapine, an atypical neuroleptic agent, with
haloperidol, a more traditional neuroleptic. These studies will search
for possible differences in effects on the extrapyramidal system (caudate
nucleus) and the limbic system (amygdala).
- Carry out preliminary development on several "orphan drug"
projects in which promising data is available (e.g., for drugs affecting
muscarinic, sigma, and serotonin systems). These projects should be advanced
to see if novel or therapeutically promising compounds may result.
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