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structure-based design, synthesis, and in vivo antinociceptive effects of selective a 1 adenosine receptor agonists
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نویسنده
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petrelli r. ,scortichini m. ,belardo c. ,boccella s. ,luongo l. ,capone f. ,kachler s. ,vita p. ,del bello f. ,maione s. ,lavecchia a. ,klotz k.-n. ,cappellacci l.
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منبع
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journal of medicinal chemistry - 2018 - دوره : 61 - شماره : 1 - صفحه:305 -318
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چکیده
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Our previous work discovered that combining the appropriate 5'- and n 6 -substitution in adenosine derivatives leads to the highly selective human a 1 adenosine receptor (ha 1 ar) agonists or highly potent dual ha 1 ar agonists and ha 3 ar antagonists. in order to explore novel dual adenosine receptor ligands, a series of n 6 -substituted-5'-pyrazolyl-adenosine and 2- chloro-adenosine derivatives were synthesized and assayed in vitro at all ars. the n 6 -(±)-endo-norbornyl derivative 12 was the most potent and selective at a 1 ar and effective as an analgesic in formalin test in mice, but none of the 5'-pyrazolyl series compounds showed a dual behavior at ha 1 and ha 3 ar. molecular modeling studies rationalized the structure-activity relationships and the selectivity profiles of the new series of a1ar agonists. interestingly, an unexpected inverted binding mode of the n 6 -tetrahydrofuranyl derivative 14 was hypothesized to explain its low affinity at a 1 ar.
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آدرس
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university of camerino, school of pharmacy, medicinal chemistry unit, italy, university of camerino, school of pharmacy, medicinal chemistry unit, italy, university of campania l. vanvitelli, department of experimental medicine, section of pharmacology l. donatelli, italy, university of campania l. vanvitelli, department of experimental medicine, section of pharmacology l. donatelli, italy, university of campania l. vanvitelli, department of experimental medicine, section of pharmacology l. donatelli, italy, university of naples federico ii, department of pharmacy, drug discovery laboratory, italy, universität würzburg, institut für pharmakologie and toxikologie, germany, university of camerino, school of pharmacy, medicinal chemistry unit, italy, university of camerino, school of pharmacy, medicinal chemistry unit, italy, university of campania l. vanvitelli, department of experimental medicine, section of pharmacology l. donatelli, italy, university of naples federico ii, department of pharmacy, drug discovery laboratory, italy, universität würzburg, institut für pharmakologie and toxikologie, germany, university of camerino, school of pharmacy, medicinal chemistry unit, italy
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Authors
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