Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“…Moreover, to favor the binding to OX1-R, the 6-amide side chain should be oriented toward the lower side of the C-ring. 67,69 Analogous results were obtained with the 14-dehydrated (16a/16b) and 14-H (17a/17b) analogs of the derivatives lacking the 4,5-epoxy ring YNT-816 and F I G U R E 12 Evaluation of the role of the configuration of the 6-amide side chain and of the presence of the 4,5-epoxy ring in the OX1-R activity and selectivity of lead YNT-707. [Color figure can be viewed at wileyonlinelibrary.com] YNT-817, respectively (Figure 13).…”

“…Over the years, 67–71 the authors focused on characterizing how and why this lead compound binds to OX1‐R, discovered the key elements required for optimal binding, and understood which changes lead to affinity at KOR and which lead to affinity at OX1‐R. As already discussed in the Section 3.2.1, when the 6‐amide chain has an upward facing conformation, the compound is able to bind at OX1‐R, while when the 6‐amide chain has a downward facing conformation, the affinity at KOR greatly increases to the detriment of the OX1‐R binding (Figure 15).…”

“…66 Then, the roles of the orientation of the 6-amide side chain and of the presence of the 4,5-epoxy ring were evaluated. The 6α-isomer of YNT-707 (compound YNT-1369, Figure 12) showed a marked decrease in OX1-R antagonist potency, while, interestingly, between the derivatives without the 4,5-epoxy ring, the 6α-isomer YNT-816 (Figure 12) was a slightly more potent OX1-R antagonist than the 6β-isomer YNT-817 (Figure 12), even if it also showed a weak activity for OX2-R. 67 In these derivatives, the removal of the 3-methoxy substituent was detrimental for OX1-R affinity only when the amide group is in position 6β (compare 15b to 15a, Figure 12), confirming that the 3-methoxy group is an essential feature for the 6β-compounds. 68 The hydroxy group in position 14 of YNT-707 and YNT-1369 significantly affected the OX1-R antagonist activity.…”

“…Binding studies demonstrated that the compound not only binds to the dimer, but also to the KOR and OX1-R separately, which lead to the conclusion that binding to the dimer is not the sole cause of the lack of aversion. 66 Over the years, [67][68][69][70][71] the authors focused on characterizing how and why this lead compound binds to OX1-R, discovered the key elements required for optimal binding, and understood which changes lead to affinity at KOR and which lead to affinity at OX1-R. As already discussed in the Section 3.2.1, when the 6-amide chain has an upward facing conformation, the compound is able to bind at OX1-R, while when the 6-amide chain has a downward facing conformation, the affinity at KOR greatly increases to the detriment of the OX1-R binding (Figure 15). The 5-membered D-nor-naltrexone ring cannot be a substituted for the 6-membered ring, because the lone pair at 17-N must have an axial position for binding at OX1-R, a feature that is lost when substituted for the 5-membered ring, though binding at KOR did improve with this feature.…”

Therapeutics development for addiction: Orexin-1 receptor antagonists

“…In follow-up studies the same group investigated several positions for their importance for the OX1 potency and selectivity (Ohrui et al, 2018;Yamamoto et al, 2017). It was discovered that the 3-methoxy was important for OX1 activity as its removal resulted in markedly reduced potency.…”