期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 23, 页码 9901-9914出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501021n
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资金
- National Institutes of Health [R01HL077707]
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]
(N)-Methanocarba adenosine 5'-methyluronamides containing 2-arylethynyl groups were synthesized as A3 adenosine receptor (AR) agonists and screened in vivo (po) for reduction of neuropathic pain. A small N-6-methyl group maintained binding affinity, with human > mouse A3AR and MW < 500 and other favorable physicochemical properties. Emax (maximal efficacy in a mouse chronic constriction injury pain model) of previously characterized A3AR agonist, 2-(3,4-difluorophenylethynyl)-N-6-(3-chlorobenzyl) derivative 6a, MRS5698, was surpassed. More efficacious analogues (in vivo) contained the following C2-arylethynyl groups: pyrazin-2-yl 23 (binding Ki, hA(3)AR, nM 1.8), fur-2-yl 27 (0.6), thien-2-yl 32 (0.6) and its 5-chloro 33, MRS5980 (0.7) and 5-bromo 34 (0.4) equivalents, and physiologically unstable ferrocene 36, MRS5979 (2.7). 33 and 36 displayed particularly long in vivo duration (>3 h). Selected analogues were docked to an A3AR homology model to explore the environment of receptor-bound C2 and N-6 groups. Various analogues bound with mu M affinity at off-target biogenic amine (M-2, 5HT(2A), beta(3), 5HT(2B), 5HT(2C), and alpha(2C)) or other receptors. Thus, we have expanded the structural range of orally active A3AR agonists for chronic pain treatment.
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