Translation-focused approaches to GPCR drug discovery for cognitive impairments associated with schizophrenia

Cassandra J. Hatzipantelis, Monica Langiu, Teresa H. Vandekolk, Tracie L. Pierce, Jess Nithianantharajah, Gregory D. Stewart, Christopher J. Langmead

Research output: Contribution to journalReview ArticleResearchpeer-review

2 Citations (Scopus)

Abstract

There are no effective therapeutics for cognitive impairments associated with schizophrenia (CIAS), which includes deficits in executive functions (working memory and cognitive flexibility) and episodic memory. Compounds that have entered clinical trials are inadequate in terms of efficacy and/or tolerability, highlighting a clear translational bottleneck and a need for a cohesive preclinical drug development strategy. In this review we propose hippocampal-prefrontal-cortical (HPC-PFC) circuitry underlying CIAS-relevant cognitive processes across mammalian species as a target source to guide the translation-focused discovery and development of novel, procognitive agents. We highlight several G protein-coupled receptors (GPCRs) enriched within HPC-PFC circuitry as therapeutic targets of interest, including noncanonical approaches (biased agonism and allosteric modulation) to conventional clinical targets, such as dopamine and muscarinic acetylcholine receptors, along with prospective novel targets, including the orphan receptors GPR52 and GPR139. We also describe the translational limitations of popular preclinical cognition tests and suggest touchscreen-based assays that probe cognitive functions reliant on HPC-PFC circuitry and reflect tests used in the clinic, as tests of greater translational relevance. Combining pharmacological and behavioral testing strategies based in HPC-PFC circuit function creates a cohesive, translationfocused approach to preclinical drug development that may improve the translational bottleneck currently hindering the development of treatments for CIAS.

Original languageEnglish
Pages (from-to)1042–1062
Number of pages21
JournalACS Pharmacology & Translational Science
Volume3
Issue number6
DOIs
Publication statusPublished - 28 Oct 2020

Keywords

  • Cognitive impairment
  • Drug discovery
  • GPCRs
  • Hippocampal-prefrontal cortical circuitry
  • Preclinical
  • Rodent touchscreen
  • Schizophrenia

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