Screening of Small Molecule Libraries to Identify Trace Amine Receptor Ligands Active in Treatment of PD

For the treatment of Parkinson’s disease, no direct dopamine agonist compares in efficacy to levodopa, suggesting that levodopa itself or its metabolites may affect targets in addition to dopamine receptors to fully manifest its effects. Endogenous amines of unknown function, trace amines, that are structurally related to dopamine and other monoamines are normally found at low concentrations in the brain.

The recently discovered trace amine receptors represent attractive potential mediators for these additional putative targets of levodopa. These new receptors can be activated by a variety of endogenous and exogenous compounds including trace amines, amphetamines and monoamine metabolites and are associated with the neuronal circuitry that controls movement.

We will first identify novel ligands of trace amine receptors in vitro by high-content, high-throughput screening of available small molecule libraries (50,000 compounds) using the cell-based Transfluor® assay. This assay, developed in our lab, is based on the ability of an activated receptor to interact with a fluorescently labeled signaling molecule. We will then screen the newly identified trace amine ligands for their efficacy in a novel pre-clinical model of Parkinson’s disease that we have specifically developed for this purpose (DDD mice). DDD mice reproduce with great fidelity all major Parkinson’s-related behavioral manifestations, and permit the possibility of large-scale drug screening in vivo for identification of compounds that may induce movement in the absence of endogenous dopamine.

Drugs active at trace amine receptors could potentially enable the nonfunctional dopamine pathways to be circumvented. The predicted effects of such compounds would be restoration of movement in a dopamine-independent fashion and/or enhancement in the efficacy of L-DOPA on the dopamine circuitry with potential for reduction of the side effects of L-DOPA therapy.