Pramipexole Derivatives as Potent and Selective Dopamine D3 Receptor Agonists with Improved Human Microsomal Stability |
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| Authors: | Dr. Jianyong Chen Dr. Cheng Jiang Prof. Beth Levant Dr. Xiaoqin Li Dr. Ting Zhao Dr. Bo Wen Dr. Ruijuan Luo Prof. Duxin Sun Prof. Shaomeng Wang |
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| Affiliation: | 1. Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109 (USA);2. Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160‐7417 (USA);3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 (USA) |
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| Abstract: | Herein we report the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective agonists of the dopamine‐3 (D3) receptor. A number of these new compounds bind to the D3 receptor with sub‐nanomolar affinity and show excellent selectivity (>10 000) for the D3 receptor over the D1 and D2 receptors. For example, compound 23 (N‐(cis‐3‐(2‐(((S)‐2‐amino‐4,5,6,7‐tetrahydrobenzo[d]thiazol‐6‐yl)(propyl)amino)ethyl)‐3‐hydroxycyclobutyl)‐3‐(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)benzamide) binds to the D3 receptor with a Ki value of 0.53 nM and shows a selectivity of >20 000 over the D2 and D1 receptors in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes. Moreover, in vitro functional assays showed it to be a full agonist for the human D3 receptor. |
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| Keywords: | agonists dopamine‐3 microsomal stability pramipexole derivatives receptors |
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