Functional Selectivity: A Novel approach for CNS Drug Discovery

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): In classical pharmacology, an agonist activates a[unreadable] single linear signal transduction pathway, whereas an antagonist blocks the action of the agonist and[unreadable] possesses no intrinsic activity. A rapidly evolving idea is that a given receptor, through various ligand induced[unreadable] functional conformations, can engage multiple modalities through interaction with different[unreadable] signaling partners. Hence, a given ligand can bind a receptor and act as an antagonist for one signaling[unreadable] pathway while serving as an agonist at another or vice versa. This property is established for several G[unreadable] protein-coupled receptors ? the most important targets for therapeutic intervention. Importantly, none[unreadable] of the drugs in clinical use have been developed with these multiple signaling considerations in mind.[unreadable] Additionally, agonists and antagonists are rarely completely selective and, for a given receptor, may[unreadable] alter signaling by influencing various receptor-mediated processes such as interaction with G proteins,[unreadable] desensitization, internalization, down-regulation, and receptor-mediated scaffolding of non-G protein[unreadable] signaling components. The physiological relevance of these properties is not fully appreciated. Thus,[unreadable] identifying the FUNCTIONAL SELECTIVITY of compounds may help reveal not only distinct biological[unreadable] processes, but also specific functional outcomes. Currently, the relevance of functional selectivity to[unreadable] psychiatry is unknown. This is particularly important for atypical antipsychotics, where dopamine (DA)[unreadable] D2 and 5-HT2A serotonin receptor antagonism is essentially a prerequisite for all these drugs;[unreadable] however, their other intrinsic activities are obscure. The overall goal of the proposed research is to[unreadable] elucidate signal transduction mechanisms that are essential for antipsychotic efficacy in preclinical[unreadable] genetic and pharmacological mouse models of schizophrenia-like behaviors. The behavioral core will[unreadable] analyze effects of anti psychotics on locomotion, prepulse inhibition, latent inhibition, and social[unreadable] behavior in DA transporter knockout, NMDA NR1-subunit knockdown, and C57BL/6 mice treated with[unreadable] amphetamine or phencyclidine to reproduce schizophrenia-like states. Molecular fingerprinting studies[unreadable] will be performed to analyze effects of antipsychotic drugs on various signal transduction modalities[unreadable] that include the PKA and DARPP-32, AktiGSK, PLC, and ERK pathways. Understanding the relevance[unreadable] of functional selectivity of anti psychotics may provide novel targets with fewer side-effects, greater[unreadable] therapeutic selectivity, and enhanced efficacy for treating individuals with schizophrenia. [unreadable] [unreadable]