Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity.

Journal of Medicinal Chemistry
Swati BiswasAloke K Dutta

Abstract

In the current report, we extend the SAR study on our hybrid structure 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol further to include heterocyclic bioisosteric analogues. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. The highest binding affinity and selectivity for D3 receptors were exhibited by (-)-34 (Ki=0.92 nM and D2/D3=253). In the functional GTPgammaS binding assay, (-)-34 exhibited full agonist activity with picomolar affinity for D3 receptor with high selectivity (EC50=0.08 nM and D2/D3=248). In the in vivo rotational study, (-)-34 exhibited potent rotational activity in 6-OH-DA unilaterally lesioned rats with long duration of action, which indicates its potential application in neuroprotective treatment of Parkinson's disease.

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Citations

Mar 21, 2016·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Fahd DholkawalaAloke K Dutta
Mar 6, 2010·Annals of the New York Academy of Sciences·Christian A Heidbreder, Amy H Newman
Dec 17, 2014·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·S KasselH Stark
Dec 30, 2014·European Journal of Medicinal Chemistry·Chandra Bhushan MishraManisha Tiwari
Jan 25, 2018·Expert Opinion on Drug Discovery·Ivana CacciatoreAntonio Di Stefano

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