ACT-335827

In rodents, orexin neuropeptides regulate motivation and reward-seeking via orexin 1 receptor (OX1R) signaling in the mesolimbic dopaminergic system. This role is clearly established for rewards inherent to drugs of abuse but less so for natural rewards. Reported effects of the selective OX1R antagonist (SO1RA) SB-334867 on motivation for palatable food are ambiguous. In our experimental conditions neither SB-334867, nor two additional, structurally different SO1RAs, ACT-335827 and the clinical development candidate nivasorexant, affected effort-based responding for sucrose in rats. The positive control lisdexamfetamine, approved for psychiatric disorders associated with altered reward sensitivity such as binge eating disorder, increased effort-based responding.

In this study, OX₁R QSAR models were constructed based on the pIC₅₀ values of 36 pyrazoylethylbenzamide derivativesResults indicated that the models have good reliability and predictability.Furthermore, 3D-QSAR contour maps reveal that the bioactivity of antagonists is most affected by hydrogen bond receptors.Mol. docking showed significant hydrogen bonds between key residues and OX₁R pocket were determinedSeven new more selective OX₁R antagonists were designed based on the contour maps and mol. docking results.The results of ADME prediction illustrated that the designed compounds had potential druggability and that the selectivity index value was higher than that of template mol. 33.The mol. dynamics simulation results of compound 33 and DS01 indicated that their stability can be attributed to the hydrogen bonds between the nitrogen atom in the R₁ region, the fluorine atom in the R₄ region and the protein pockets.Four new skeletal antagonists were screened from the ZINC12 database based on the pharmacophore model.The mol. docking indicated that the screened compounds formed addnl. hydrogen bond interaction with residues GLN176 and ARG322 of OX₁R.The present study could offer theor. guidance for future structural optimization, design, and synthesis of more selective OX₁R antagonists.Designed and screened compounds might also be as candidate compounds for related research groups.