Synthesis and Structure-Activity Relationships of Triazaspirodecanone Derivatives as Nociceptin/Orphanin FQ Receptor Ligands

• Published in: Chemical biology & drug design Vol. 86; no. 4; pp. 447 - 458
• Main Authors: Corrado, Sandra, Battisti, Umberto M., Sorbi, Claudia, Tait, Annalisa, Malfacini, Davide, Camarda, Valeria, Calò, Girolamo, Brasili, Livio
• Format: Journal Article
• Language: English
• Published: HOBOKEN Blackwell Publishing Ltd 01.10.2015; Wiley
• Subjects: agonists; Animals; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Biochemistry & Molecular Biology; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Ligands; Molecular Structure; NOP ligands; ORL-1; Pharmacology & Pharmacy; Receptors, Opioid - agonists; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; spiroxatrine; Structure-Activity Relationship; triazaspirodecanone; ORPHANIN-FQ; ANTAGONIST; ANALOGS; ORL1; PEPTIDE; spiroxatrine; NOP ligands; ORL-1; agonists; PROFILE; PHARMACOLOGY; triazaspirodecanone; AGONIST
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12505

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 CH2 linked to the 1‐phenyl‐1,3,8‐triaza‐spiro[4.5]decan‐4‐one portion. Moreover, cis diastereoisomers of the hydroxyl derivatives4 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. Substitution of the 1,4‐benzodioxane moiety of spiroxatrine with a 4‐hydroxy‐chromane portion gives compound cis‐4, a good candidate to generate a new class of NOP agonists.