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Effects of a novel mGlu2/3 receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid

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Abstract

Rationale

Accumulating evidence suggests that the primary symptoms of schizophrenia may be associated with altered central glutamate transmission. LY2140023 monohydrate is the methionine prodrug of the selective mGlu2/3 receptor agonist LY404039 and is currently being assessed for the treatment of schizophrenia.

Objective

The objective of this study was to evaluate the central pharmacological activity of LY2140023 monohydrate in preclinical and clinical studies.

Methods

Effects on neurotransmitter/metabolite concentrations were assessed in male rats following single oral doses of LY2140023 monohydrate (microdiasylates from the prefrontal cortex), single intraperitoneal injection of LY404039 [cerebrospinal fluid (CSF)], or LY2140023 monohydrate dosed once daily for 7 days (CSF). A clinical study in 16 healthy subjects assessed the effects of LY2140023 monohydrate 40 mg orally twice daily for 14 days in lumbar CSF.

Results

Rat studies: Acute dosing with LY2140023 monohydrate resulted in significant dose-dependent increases in extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), but not 5-hydroxyindoleacetic acid (5-HIAA), in the prefrontal cortex. LY2140023 monohydrate dosing for 7 days elevated the concentrations of HVA in CSF, while acutely dosed LY404039 increased the concentrations of DOPAC, HVA, and methoxy-hydroxyphenylglycol (MHPG), but not 5-HIAA. Clinical study: Significant increases were seen for DOPAC, HVA, 5-HIAA, and MHPG in the CSF of subjects receiving LY2140023 monohydrate, but not placebo.

Conclusions

LY2140023 monohydrate and/or LY404039 dosing potently affected dopamine turnover and also significantly affected serotonin turnover in the human and rat central nervous systems. The measurement of biogenic amine metabolites such as DOPAC and HVA may serve as useful biomarkers of LY2140023 monohydrate and/or LY404039 central pharmacodynamic activity.

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Acknowledgments

This study was funded by Eli Lilly and Company. Dan Czilli and Linda Thompson are acknowledged for assistance with rat CSF collections. Kalpana Merchant, PhD, Lilly Research Labs, is acknowledged for valuable contributions to the design of the initial rat CSF study. Cynthia Fuller, PhD, and Thomas Melby, MS (both of i3, Ann Arbor, MI), assisted with the development of this manuscript. All experiments complied with the current laws of the country in which they were performed.

Disclosure/conflict of interest

All authors were employees and/or shareholders of Eli Lilly and Company at the time this work was performed.

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Authors and Affiliations

  1. Lilly-NUS Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD 11), National University of Singapore, 10 Medical Drive, Singapore, 117597, Singapore

    Stephen Lowe & Mary Ho

  2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

    Robert Dean, Fanni Natanegara, Shelby Anderson, Mosun Ayan-Oshodi, David McKinzie, Kenneth Perry & Kjell Svensson

  3. Eli Lilly and Company, Greenfield Laboratories, Greenfield, IN, USA

    Bradley Ackermann & James Eckstein

  4. Lilly Research Laboratories, Windlesham, Surrey, UK

    Kimberley Jackson & Eunice Yuen

Authors
  1. Stephen Lowe
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  2. Robert Dean
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  3. Bradley Ackermann
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  4. Kimberley Jackson
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  5. Fanni Natanegara
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  6. Shelby Anderson
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  7. James Eckstein
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  8. Eunice Yuen
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  9. Mosun Ayan-Oshodi
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  10. Mary Ho
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  11. David McKinzie
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  12. Kenneth Perry
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  13. Kjell Svensson
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Corresponding author

Correspondence to Stephen Lowe.

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Lowe, S., Dean, R., Ackermann, B. et al. Effects of a novel mGlu2/3 receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid. Psychopharmacology 219, 959–970 (2012). https://doi.org/10.1007/s00213-011-2427-9

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  • DOI: https://doi.org/10.1007/s00213-011-2427-9

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