Design and synthesis of dual 5-HT_1A and 5-HT₇ receptor ligands

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• 作者：Edward Ofori^a ; Xue Y. Zhu^a ; Jagan R. Etukala^a ; Kwakye Peprah^a ; Kamanski R. Jordan^a ; Adia A. Adkins^a ; Barbara A. Bricker^a ; Hye J. Kang^b ; ^c ; Xi-Ping Huang^b ; ^c ; Bryan L. Roth^b ; ^c ; ^d ; Seth Y. Ablordeppey^a ;
• 关键词：Dual receptor ligands ; Multi-receptor targeting ; CNS ligands ; Serotonin receptors ; 5-HT1A receptor and 5-HT7 receptor ligands
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：24
• 期：16
• 页码：3464-3471
• 全文大小：1746 K

文摘

5-HT_1A and 5-HT₇ receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT₇ receptor ligand culminating in the identification of several dual 5-HT_1A and 5-HT₇ receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.