Ofori Edward, Zhu Xue Y, Etukala Jagan R, Peprah Kwakye, Jordan Kamanski R, Adkins Adia A, Bricker Barbara A, Kang Hye J, Huang Xi-Ping, Roth Bryan L, Ablordeppey Seth Y
Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
Bioorg Med Chem. 2016 Aug 15;24(16):3464-71. doi: 10.1016/j.bmc.2016.05.053. Epub 2016 May 27.
5-HT1A 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-HT1A 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.
5-羟色胺1A（5-HT1A）和5-羟色胺7（5-HT7）受体最近成为了讨论的焦点，部分原因是它们在诸如抑郁症、睡眠障碍和精神分裂症等主要中枢神经系统疾病的病因中起着重要作用。作为我们寻找这些受体的双靶点配体的一部分，我们对一种选择性5-HT7受体配体进行了系统修饰，最终鉴定出了几种5-HT1A和5-HT7受体双靶点配体。化合物16是一种四氢异喹啉（THIQ）的丁酰苯衍生物，被确定为对两种受体具有低纳摩尔结合亲和力的最有效药物。有趣的是，化合物16对其他临床相关的多巴胺受体也表现出中等亲和力。因此，预计化合物16可作为进一步开发的先导物，以寻找有潜力治疗中枢神经系统源性疾病的新配体。
