Back to the Team Dopamine Home Page Together, Members of Team Dopamine represent a range of biomedical disciplines. As individuals, they have made widely recognized strides in their own research. Their basic neurobiological research has converged towards a new collaborative project that has particular importance to drug development. The team confers with neuroscientists and medicinal chemists at Hoechst-Rouse Pharmaceuticals, Inc. (HRPI) to develop innovative drugs for the treatment of dopamine-related neurological and psychiatric disorders.
Team Dopamine's individual research contributions include molecular design and characterization of new drugs that are isoform- and/or function-selective, the study of the mechanisms responsible for drug binding and receptor activation or inhibition, and the involved mechanisms of synaptic transmission and receptor occupation. The accomplishments of Team Dopamine's five laboratories fuel the enterprise, contributing novel lead compounds in several areas, original hypotheses relevant to both basic research and drug development, and technical approaches that can provide a better understanding of how existing drugs work.
The Dopamine Team's discovery research has already led to a new way to understand the mechanisms of dopamine neurotransmission. In its nascent stages, the Team terms this concept the "functional selectivity hypothesis." The "functional selectivity hypothesis" states that physiological or biochemical changes caused by receptor occupation are a function of not only the molecular isoform of the target receptor and the intrinsic character of the drug of interest, but also of the cellular milieu in which the receptor is located.
The functional selectivity hypothesis has important ramifications. It suggests that some drugs may have markedly different functional consequences depending on the location of the target receptor isoform. In the most extreme case, a drug may be an agonist in one brain region, and an antagonist in another, even while acting on the same molecular isoform. Recent studies by "Team Dopamine" have provided the data supporting such an idea. If true, there are obvious consequences for drug development. For example, the hypothesis suggests that a single functional screen of a new drug in a cloned cell fine may not adequately predict activity in the intact brain and, ultimately, in the clinic. Moreover, with candidate structures that cause such functional differentiation, drugs with an appropriate mix of activity could be designed.
Our research efforts begin with exploring the atomic and molecular factors that influence why two drugs with similar affinity cause different functional consequences at the same molecular isoforms. Beginning with computational chemistry and molecular modeling, an iterative approach is used that includes synthesis of target compounds followed by sophisticated functional evaluation. These data are then used to refine the models to yield a better understanding of the data and new generations of ligands. Such drugs then become important tools in the study of nervous system function.
Members of "Team Dopamine" utilize several powerful approaches, outlined below, to address the very mechanisms that are, ultimately, related to the etiology and therapy of important psychiatric and neurological disorders.