| Autor: |
St Onge CM; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23219, United States., Pagare PP; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23219, United States., Zheng Y; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23219, United States., Arriaga M; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Stevens DL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Mendez RE; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Poklis JL; Department of Pharmaceutics, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Halquist MS; Department of Pharmaceutics, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Selley DE; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Dewey WL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Banks ML; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States., Zhang Y; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23219, United States.; Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.; Institute for Drug and Alcohol Studies, 203 East Cary Street, Richmond, Virginia 23298, United States. |
| Abstrakt: |
Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23 , showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain. |
