Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton

Abstract

A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist 28c (EC50 = 9.21 nM for OX2R, 148 nM for OX1R). The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.

Computational Analysis of Fully Activated Orexin Receptor 2 Across Various Thermodynamic Ensembles with Surface Tension Monitoring

“…C107 2.57 , F227 5.42 , D211 4.84 , H350 7.39 ) but exclusivism of these interactions as the statedeterminants for OX2R agonism is still reluctant. [41][42][43][44][45] Regarding the in silico studies reported by Hong et al, the molecular dynamics simulations of OX2R-OXB in a pure POPC bilayer, taking 1 µs in NPT/OPLS3e ensemble with TIP3P water models and positional restriction force of 5 kcal/mol/Å 2 imposed on selected heavy atoms, confirmed nearly a whole-run stable RMSD for heavy atoms forming the OX2R-OXB interface. 27 In agreement with other in silico studies, Hong et al accepted the hypothesis that GPCRs occur in several elastic metastates on the activation potential coordinate and GPCR agonists rather shift the equilibrium towards populating more the active state than cause a conformational transition to a local energetic minimum, that is in the case of OX2R rotated outswing of TM6, upward movement of TM3, and centripetal shift of TM2.…”

Design and synthesis of orexin 1 receptor-selective agonists

“…31 Moreover, we have independently reported (R)-2, which is derived from a naphthalene-type OX2R agonist and exhibits highly potent agonist activity for both receptors (EC50 = 13.5 nM for OX1R, 0.579 nM for OX2R). 32,33 Despite the significant progress in the development of OX2R-selective and dual OX1/2R agonists, no OX1R-selective agonists have been reported so far. ).…”