Functional Selectivity: A Novel approach for CNS Drug Discovery

  • Mailman, Richard (PI)
  • Roth, Bryan (PI)
  • Caron, Marc G. (PI)
  • Caron, Marc G. (CoI)
  • Wetsel, William (PI)
  • Jian, Jin (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): 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 several G protein-coupled receptors ? the most important targets for therapeutic intervention. Importantly, none of the drugs in clinical use 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 (DA) D2 and 5-HT2A serotonin receptor antagonism is essentially a prerequisite for all these drugs; however, their other intrinsic activities are obscure. The overall goal of the proposed research is to elucidate signal transduction mechanisms that are essential for antipsychotic efficacy in preclinical genetic and pharmacological mouse models of schizophrenia-like behaviors. The behavioral core will analyze effects of anti psychotics on locomotion, prepulse inhibition, latent inhibition, and social behavior in DA transporter knockout, NMDA NR1-subunit knockdown, and C57BL/6 mice treated with amphetamine or phencyclidine to reproduce schizophrenia-like states. Molecular fingerprinting studies will be performed to analyze effects of antipsychotic drugs on various signal transduction modalities that include the PKA and DARPP-32, AktiGSK, PLC, and ERK pathways. Understanding the relevance of functional selectivity of anti psychotics may provide novel targets with fewer side-effects, greater therapeutic selectivity, and enhanced efficacy for treating individuals with schizophrenia.
StatusFinished
Effective start/end date9/28/074/30/18

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Ligands
Dopamine D2 Receptors
Antipsychotic Agents
Schizophrenia
Signal Transduction
Pharmaceutical Preparations
Research
Pharmacology
Biological Phenomena
Receptor, Serotonin, 5-HT2A
Phencyclidine
Dopamine
Dopamine Plasma Membrane Transport Proteins
MAP Kinase Signaling System
Social Behavior
Therapeutic Uses
Amphetamine
N-Methylaspartate
Locomotion
G-Protein-Coupled Receptors