In classical pharmacology, an agonist activates a single linear signal transduction pathway, whereas an antagonist blocks the action of the agonist and possesses no intrinsic activity. A rapidly evolving idea is that a given receptor, through various ligand-induced functional conformations, can engage multiple modalities through interaction with different signaling partners. Hence, a given ligand can bind a receptor and act as an antagonist for one signaling pathway while serving as an agonist at another or vice versa. This property is established for a number of G protein-coupled receptors. Importantly, none of the drugs in clinical use today have been developed with these multiple signaling considerations in mind. Additionally, agonists and antagonists are rarely completely selective and, for a given receptor, may alter signaling by influencing various receptor-mediated processes such as interaction with G proteins, desensitization, internalization, down-regulation, and receptor-mediated scaffolding of non-G protein signaling components. The physiological relevance of these properties is not fully appreciated. Thus, identifying the FUNCTIONAL SELECTIVITY of compounds may help reveal not only distinct biological processes, but also specific functional outcomes. Currently, the relevance of functional selectivity to psychiatry is unknown. This is particularly important for atypical antipsychotics, where dopamine D2 receptor antagonism is essentially a prerequisite for all these drugs;however, their other intrinsic activities are obscure. The overall goal of the U19 is to elucidate signal transduction mechanisms that are essential for antipsychotic efficacy in various relevant animal models. This proposed supplement brings to the funded U19 the critical capability of creating novel compounds with unprecedented patterns of functional selectivity for elucidating the key signal transduction pathways essential for antipsychotic actions. The U19 investigators as a collaborative group will carry out ligand design and synthesis, comprehensive in vitro profiling, and in vivo behavioral profiling in a synergistic manner to discover novel and functionally selective antipsychotic drug candidates that are more effective in animal models compared to existing atypical antipsychotics.
Understanding of the role of functional selectivity and the signal transduction pathways that are critical to antipsychotic actions will speed the discovery and development of safer and more effective new therapeutics for schizophrenia and other related psychiatric disorders.
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