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The broad-spectrum antiemetic effects ETI-385 result from stimulation of 5-HT1A and 5-HT1D receptors

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Abstract

In the present study, we describe how a nonstoichiometric ratio of the isomers of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) produce a broad-spectrum of antiemetic effects in cats and shrews. Determination of the receptor profile of the isomers and testing them separately in cats revealed superior antiemetic effects but severe defensive behavior with the R isomer compared with the S isomer. Differing ratios yielded the best results with the 1:8 (R–S) ratio producing a drug more potent than DPAT and with negligible defensive behavior side effects. Studies with selective 5-HT1D ligands led to the conclusion that this site contributes antiemetic efficacy but is not related to defensive behavior, which is most likely a consequence of 5-HT7 receptor activation. ETI-385 was effective in preventing emetic responses to provocative motion, drugs acting at the chemical trigger zone and cisplatin in both cats and shrews. The results support a clinical trial of this drug for antiemetic effects.

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Acknowledgments

Special thanks to S. Mexal, K. Senson, M.A. Stoddard, E. Sung, E.A. Smith, S. Spitak, A. Braddock, A. Furman and M.Z. Kounnas for their expert assistance. Portion of the work was funded by the Research Incentive Fund awarded by Wright State University to JBL.

Conflict of interest

The use of ETI-385 for the treatment of emesis in humans is under a pending patent owned by JBL and DRH.

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Authors and Affiliations

  1. Department of Pharmacology, Wright State University, Dayton, OH, USA

    J. B. Lucot, R. E. L. Brame & T. L. Garrett

  2. Epiomed Therapeutics, LLC, Laguna Hills, CA, USA

    E. H. Pfadenhauer, A. Kumar, D. B. Fick & D. R. Helton

Authors
  1. J. B. Lucot
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  2. R. E. L. Brame
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  3. T. L. Garrett
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  4. E. H. Pfadenhauer
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  5. A. Kumar
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  6. D. B. Fick
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  7. D. R. Helton
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Correspondence to J. B. Lucot.

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Lucot, J.B., Brame, R.E.L., Garrett, T.L. et al. The broad-spectrum antiemetic effects ETI-385 result from stimulation of 5-HT1A and 5-HT1D receptors. Exp Brain Res 232, 2699–2707 (2014). https://doi.org/10.1007/s00221-014-4004-z

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  • DOI: https://doi.org/10.1007/s00221-014-4004-z

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