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Related Experiment Videos

5-hydroxytryptamine2A receptor inverse agonists as antipsychotics.

D M Weiner1, E S Burstein, N Nash

  • 1ACADIA Pharmaceuticals Inc., San Diego, California 92121, USA. dweiner@acadia-pharm.com

The Journal of Pharmacology and Experimental Therapeutics
|September 19, 2001
PubMed
Summary

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Antipsychotics primarily target dopamine D2 receptors but also act as potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. This dual action influences efficacy and side effects, guiding new drug development.

Area of Science:

  • Neuropharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • Monoaminergic G-protein-coupled receptors (GPCRs) are key targets for central nervous system (CNS) drugs.
  • Understanding the precise receptor interactions of existing drugs is crucial for developing safer and more effective therapies.

Purpose of the Study:

  • To pharmacologically profile a broad range of CNS compounds, particularly antipsychotics, across various monoaminergic GPCRs.
  • To elucidate the relationship between receptor activity, antipsychotic efficacy, and extrapyramidal side effects (EPS).
  • To identify novel inverse agonists for the 5-hydroxytryptamine (5-HT)2A receptor.

Main Methods:

  • Cell-based functional assays were employed to determine agonist, antagonist, and inverse agonist activities.

Related Experiment Videos

  • Pharmacological profiling of 40 antipsychotics at multiple monoaminergic GPCR subtypes.
  • High-throughput screening of a diverse chemical library for 5-HT2A inverse agonist activity.

    • Main Results:

    • Most antipsychotics are potent dopamine D2 receptor antagonists and surprisingly potent 5-HT2A receptor inverse agonists.
    • Higher D2 receptor potency correlated with increased EPS liability, while higher 5-HT2A potency was associated with atypical (EPS-sparing) agents.
    • 530 novel 5-HT2A inverse agonists were identified, including a selective compound (AC-90179) with atypical antipsychotic behavioral pharmacology.

    Conclusions:

    • The dual antagonism of D2 and inverse agonism of 5-HT2A receptors is a key feature of antipsychotic pharmacology.
    • Selective 5-HT2A inverse agonists represent a promising avenue for developing novel antipsychotic agents with improved side effect profiles.
    • AC-90179 demonstrates the potential of novel 5-HT2A inverse agonists as atypical antipsychotics.