Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

Abstract

Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OXR) (K = 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 (OXR, K = 1.36 nM; OXR, 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 OXR, which led to high OXR selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OXR antagonists.

Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

“…SRI-9342 (irreversible antagonist, Scheme 1) was synthesized in 44% yield via the reaction of naltrexone hydrochloride and trans-4-hydrazino-2-stilbazole dihydrochloride following the same procedures previously reported [18,19]. SRI-45128 (inverse agonist, Scheme 2) was synthesized in nine steps by using reported procedures [20] with a few modifications. In our alternative route, the protecting group on the phenolic hydroxyl group of naltrexone (1) was changed from methyl to benzyl to achieve overall improved yields.…”

“…On the basis of NMR, HPLC-DAD, and HRMS (mass error less than 5 ppm), all final compounds were ≥95% pure. This compound was synthesized as previously described [18,19] This compound was synthesized by a modified procedure of the reported method [20] as described below. To a suspension of naltrexone (1) (5 g, 14.6 mmol) in acetone (200 mL), benzyl bromide (2.6 mL, 21.9 mmol) and potassium carbonate (4.0 mg, 29.3 mmol) were added.…”

Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications

“…It appears that OX1R may be particularly implicated in these behaviours. A number of 1‐SORAs have been discovered (Bonaventure, Yun, et al., ; Nagase et al., ; Raheem et al., ; Stump et al., ), and currently the 1‐SORA, EORA101, is reportedly being evaluated as a potential therapeutic agent for smoking cessation (Eolas Theapeutics, ), although no clinical trials are listed on clinicaltrials.gov. A study is investigating the effects of suvorexant on cocaine craving (Table ).…”

Design and Synthesis of Novel Orexin Antagonists via Structural Simplification of the Morphinan Skeleton

“…8 Recently, we found that the κ opioid receptor agonist nalfurafine showed a moderate activity and high selectivity toward OX1R, and we also synthesized the more potent OX1R antagonist YNT-707 (1) (Figure 1). 9 In these studies, we focused on how the specific character of the 4,5-epoxy-morphinan skeleton contributes to the remarkable OX1R selectivity and studied the essential structural sites required for binding to OX1R in the morphinan compounds based on 1. Our analyses showed that the specific conformation of the N17 functional group and C6 amide side chain are essential for the OX1R activity (Figure 1).…”

“…8a-hexahydroisoquinoline-2(1H)-carboxylate(9). To a solution of 8 (13.0 g, 42.0 mmol) in MeOH (130 mL) was added 1 M aqueous NaOH solution (50 mL) and the mixture was stirred for 6.5 h at 50 °C under an argon atmosphere.…”