Structurally Constrained Hybrid Derivatives Containing Octahydrobenzo[g or f]quinoline Moieties for Dopamine D2 and D3 Receptors: Binding Characterization at D2/D3 Receptors and Elucidat

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• 作者：Dennis A. Brown ; Prashant S. Kharkar ; Ingrid Parrington ; Maarten E. A. Reith ; Aloke K. Dutta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 25, 2008
• 年：2008
• 卷：51
• 期：24
• 页码：7806-7819
• 全文大小：328K
• 年卷期：v.51,no.24(December 25, 2008)
• ISSN：1520-4804

文摘

A series of structurally constrained analogues based on hybrid compounds containing octahydrobenzo[g or f]quinoline moieties were designed, synthesized, and characterized for their binding to dopamine D2 and D3 receptors expressed in HEK-293 cells. Among the newly developed constrained molecules, trans-octahydrobenzo[f]quinolin-7-ol (8) exhibited the highest affinity for D2 and D3 receptors, the (−)-isomer being the eutomer. Interestingly, this hybrid constrained version 8 showed significant affinity over the corresponding nonhybrid version 1 (representing a constrained version of the aminotetralin structure only) when assayed under same conditions (K_i of 49.1 and 14.9 nM for 8 vs 380 and 96.0 nM for 1 at D2 and D3, respectively). Similar results were found with other lead hybrid compounds, indicating a contribution of the piperazine moiety in the observed enhanced affinity. On the basis of the data of new lead constrained derivatives and other lead hybrid derivatives developed by us, a unique pharmacophore model was proposed consisting of three pharmacophoric centers, two with aromatic/hydrophobic and one with cationic features.