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Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic–pharmacodynamic relationships

  • Translational Neurosciences - Original Article
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Abstract

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60 % inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic–pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

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Acknowledgments

We would like to thank Anita Vanaga, Christiane Güntner and Werner Feser-Zügner for their support in sarizotan analysis in biological samples and Sabrina David and Sabine Justal for their excellent technical work in the T-maze experiment. Lutz Franke and Barbara Valastro are kindly acknowledged for their contribution to the coordination of experimental activities and providing the idea of ADHD testing respectively.

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Authors and Affiliations

  1. Merz Pharmaceuticals GmbH, Alfred Wegener Strasse 2, 60438, Frankfurt/Main, Germany

    Wojciech Danysz, Claudia C. Jatzke, Sergio Greco, Ann-Kristin Jenssen & Christopher G. Parsons

  2. Brains On-Line B.V., De Mudden 16, 9747 AW, Groningen, The Netherlands

    Gunnar Flik & Andrew McCreary

  3. Rent-a-lab, Aspenhaustr. 25, 72770, Reutlingen, Germany

    Carsten Tober

  4. NeuroCode AG, Sportparkstr. 9, 35578, Wetzlar, Germany

    Wilfried Dimpfel

  5. Key-Obs SAS, 13 avenue Buffon, 45071, Orléans Cedex 02, France

    Jean C. Bizot

  6. Quillen College of Medicine, East Tennessee State University, PO Box 70577, Johnson, TN, 37614-0577, USA

    Richard Kostrzewa & Russell W. Brown

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  1. Wojciech Danysz
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  2. Gunnar Flik
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Correspondence to Wojciech Danysz.

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Danysz, W., Flik, G., McCreary, A. et al. Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic–pharmacodynamic relationships. J Neural Transm 122, 1221–1238 (2015). https://doi.org/10.1007/s00702-015-1392-6

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  • DOI: https://doi.org/10.1007/s00702-015-1392-6

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