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Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D2 and D3 Receptors

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Abstract

In elucidating the role of pharmacodynamic efficacy at D3 receptors in therapeutic effectiveness of dopamine receptor agonists, the influence of study system must be understood. Here two compounds with D3 over D2 selectivity developed in our earlier work, D-264 and D-301, are compared in dopamine receptor-mediated G-protein activation in striatal regions of wild-type and D2 receptor knockout mice and in CHO cells expressing D2 or D3 receptors. In caudate-putamen of D2 knockout mice, D-301 was ~3-fold more efficacious than D-264 in activating G-proteins as assessed by [35S]GTPγS binding; in nucleus accumbens, D-301 stimulated G-protein activation whereas D-264 did not. In contrast, the two ligands exerted similar efficacy in both regions of wild-type mice, suggesting both ligands activate D2 receptors with similar efficacy. In D2 and D3 receptor-expressing CHO cells, D-264 and D-301 appeared to act in the [35S]GTPγS assay as full agonists because they produced maximal stimulation equal to dopamine. Competition for [3H]spiperone binding was then performed to determine Ki/EC50 ratios as an index of receptor reserve for each ligand. Action of D-301, but not D-264, showed receptor reserve in D3 but not in D2 receptor-expressing cells, whereas dopamine showed receptor reserve in both cell lines. Gαo1 is highly expressed in brain and is important in D2-like receptor-G protein coupling. Transfection of Gαo1 in D3- but not D2-expressing CHO cells led to receptor reserve for D-264 without altering receptor expression levels. D-301 and dopamine exhibited receptor reserve in D3-expressing cells both with and without transfection of Gαo1. Altogether, these results indicate that D-301 has greater intrinsic efficacy to activate D3 receptors than D-264, whereas the two compounds act on D2 receptors with similar intrinsic efficacy. These findings also suggest caution in interpreting Emax values from functional assays in receptor-transfected cell models without accounting for receptor reserve.

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Acknowledgments

This work is supported by National Institute of Neurological Disorders and Stroke/National Institute of Health (NS047198, AKD) and National Institute of Health (R01-NS070715, DES).

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    1. Department of Psychiatry, Alexandria Center Life Science Room 843-H, New York University School of Medicine, 450 E 29th Street, New York, NY, 10016, USA

      Juan Zhen, Tamara Antonio & Maarten E. A. Reith

    2. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA

      Joanna C. Jacob & Dana E. Selley

    3. DKG Department of Physiology and Pharmacology, School of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA

      David K. Grandy

    4. Department of Biochemistry and Molecular Pharmacology, Alexandria Center Life Science Room 803, New York University School of Medicine, 450 E 29th Street, New York, NY, 10016, USA

      Maarten E. A. Reith

    5. Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA

      Aloke K. Dutta

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    Maarten E. A. Reith, Aloke K. Dutta and Dana E. Selley have contributed equally to this work.

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    Zhen, J., Antonio, T., Jacob, J.C. et al. Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D2 and D3 Receptors. Neurochem Res 41, 328–339 (2016). https://doi.org/10.1007/s11064-015-1808-6

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