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Synthesis and Structure–Activity Relationships of Triazaspirodecanone Derivatives as Nociceptin/Orphanin FQ Receptor Ligands
Author(s) -
Corrado Sandra,
Battisti Umberto M.,
Sorbi Claudia,
Tait Annalisa,
Malfacini Davide,
Camarda Valeria,
Calò Girolamo,
Brasili Livio
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12505
Subject(s) - nop , nociceptin receptor , chemistry , moiety , stereochemistry , diastereomer , derivative (finance) , stereoselectivity , structure–activity relationship , receptor , biochemistry , opioid , opioid peptide , in vitro , catalysis , financial economics , economics
Several spiroxatrine derivatives were synthesized and evaluated as potential NOP receptor ligands. Structural modifications of the 1,4‐benzodioxane moiety of spiroxatrine have been the focus of this research project. The structure–activity relationships that emerged indicate that the presence of an H‐bond donor group (hydroxyl group) is more favorable for NOP activity when it is positioned α with respect to the CH 2 linked to the 1‐phenyl‐1,3,8‐triaza‐spiro[4.5]decan‐4‐one portion. Moreover, cis diastereoisomers of the hydroxyl derivatives 4 and 22 show a moderately higher degree of stereoselectivity than trans isomers. In particular, the spiropiperidine derivative cis ‐ 4 has submicromolar agonistic activity, and it will be the reference compound for the design and synthesis of new NOP agonists.