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 Recept

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• 作者：Swati Biswas ; Stuart Hazeldine ; Balaram Ghosh ; Ingrid Parrington ; Eldo Kuzhikandathil ; Maarten E. A. Reith ; Aloke K. Dutta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 22, 2008
• 年：2008
• 卷：51
• 期：10
• 页码：3005 - 3019
• 全文大小：279K
• 年卷期：v.51,no.10(May 22, 2008)
• ISSN：1520-4804

文摘

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 (K_i). Functional activity of selected compounds in stimulating GTPγS 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 (K_i = 0.92 nM and D2/D3 = 253). In the functional GTPγS 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.