MK-3697

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.

Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX₁R) (K_i = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX₁R, K_i = 1.36 nM; OX₂R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX₂R, which led to high OX₁R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX₁R antagonists.