Discovery of an M -Substituted N -Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active κ-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile.

Autor: He Q; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Wei Y; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, 555 Zuchongzhi Road, Shanghai 201203, China.; School of Basic Medicine Sciences and Clinical Pharmacy, China Pharmaceutical University, No.639 Longmian Road, Nanjing 210009, China., Liu X; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Ye R; School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China., Kong L; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Li Z; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Jiang S; School of Pharmacy, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Nanjing 210023, China., Yu L; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Chai J; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, 555 Zuchongzhi Road, Shanghai 201203, China., Xie Q; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Fu W; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Wang Y; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, 555 Zuchongzhi Road, Shanghai 201203, China., Li W; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Qiu Z; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China., Liu J; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, 555 Zuchongzhi Road, Shanghai 201203, China., Shao L; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China.; State Key Laboratory of Medical Neurobiology, Fudan University, No. 138 Yixueyuan Road, Shanghai 200032, China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Aug 26; Vol. 64 (16), pp. 12414-12433. Date of Electronic Publication: 2021 Aug 13.
DOI: 10.1021/acs.jmedchem.1c01082
Abstrakt: The search for selective kappa opioid receptor (κOR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of m -substituted analogs were designed, synthesized, and assayed, resulting in the identification of compound 6c ( SLL-1206 ) as a κOR agonist with single-digit nanomolar activities. The subtype selectivity of compound 6c appeared to be a consequence of an enormous decrease in the affinity for μOR and δOR, rather than a significant increase in the affinity for κOR, which was not the case for SLL-039 , another selective and potent κOR agonist identified in our previous work. Besides reduced central nervous system effects, SLL-1206 exhibited substantially improved physicochemical and pharmacokinetic properties compared with SLL-039 , with increases of over 20-fold in aqueous solubility and approximately 40-fold in oral bioavailability in rats.
Databáze: MEDLINE