Table 1.
Effects of Hypocretin/Orexin receptors agonists and antagonists on sleep/wake in preclinical studies
| Drugs | Species/Strain | Wakefulness | Arousal state parameters | Cataplexy | Refs | |
|---|---|---|---|---|---|---|
| NREM sleep | REM sleep | |||||
| Hypocretin/Orexin receptor agonists | ||||||
| HCRTl/Orexin-A (dual OX1R/OX2R agonist) | Wildtype, OX1R KO, OX2R KO and OX1R;OX2R DKO mice | ↑ | ↓ | ↓ | N/A | [42] |
| TAK925 (HCRTR2/OX2R agonist) | C57BL/6J, OX2R KO and orexin/ataxin-3 mice | ↑ | ↓ | ↓ | ↓ | [63, 65] |
| TAK994 (HCRTR2/OX2R agonist) | Orexin/ataxin-3 mice | ↑ | ↓ | ↓ | N/R | [69] |
| YNT185 (HCRTR2/OX2R agonist) | C57BL/6J, prepro-OXKO, and OX1R;OX2R DKO and orexin/ataxin-3 mice | ↑ | ↓ | ICV: NC; IP: ↓ | ↓ | [62] |
| Dual hypocretin/orexin receptor antagonists (DORAs) | ||||||
| Almorexant (ACT-078573) | Wistar rats | ↓ | ↑ | ↑ | N/A | [15] |
| “ | Sprague-Dawley rats | ↓ | ↑ | ↑ | N/A | [74] |
| “ | Sprague-Dawley rats | ↓ | ↑ | ↑ | N/A | [48] |
| “ | Orexin/ataxin-3 and WT littermate mice | ↓ | ↑ | ↑ | ↑ | [86] |
| “ | C57BL/6NCrlCrlj mice, F344/DuCrlCrlj rats, Sprague-Dawley rats, orexin/ataxin-3 mice | ↓ | ↑ | ↑ | N/R | [87] |
| Daridorexant (ACT-541468) | Wistar rats | ↓ | ↑ | ↑ | N/R | [29] |
| Lemborexant (E2006) | C57BL/6NCrlCrlj mice, F344/DuCrlCrlj rats, Sprague-Dawley rats, orexin/ataxin-3 mice | ↓ | ↑ | ↑ | N/R | [87] |
| “ | C57BL/6J and prepro-OXKO mice | ↓ | ↑ | ↑ | ↑ | [88] |
| Suvorexant (MK-4305) | Sprague-Dawley rats | ↓ | ↑ | ↑ | N/A | [89] |
| “ | Sprague-Dawley rats | ↓ | ↑ | ↑ | N/A | [20] |
| HCRTR1/OX1R antagonists (1-SORAs) | ||||||
| ACT-335827 | Sprague-Dawley rats | NC | NC | NC | N/A | [50] |
| Compound 56 | Sprague-Dawley rats | NC | NC | NC | N/A | [90] |
| “ | OX WT mice | NR | NC | NC | N/A | [90] |
| “ | OX2R KO mice | NR | NC | ↑ | NR | [90] |
| GSK-1059865 | Sprague-Dawley rats | NC | NC | NC | N/A | [91] |
| JNJ-54717793 | Sprague-Dawley rats | NR | NC | NC | N/A | [38] |
| “ | OX WT mice | NR | NC | NC | N/A | [38] |
| “ | OX2R KO mice | NR | NC | ↑ | NR | [38] |
| JNJ-61393215 | Sprague-Dawley rats | NC | NC | NC | N/A | [55] |
| “ | OX WT mice | NR | NC | NC | N/A | [55] |
| “ | OX2R KO mice | NR | NC | ↑ | NR | [55] |
| SB-334867 | Sprague-Dawley rats | ↓ | ↑ | ↑ | N/A | [48] |
| “ | Hooded Lister rats | NC | NC | NC | N/A | [49] |
| HCRTR2/OX2R antagonists (2-SORAs) | ||||||
| EMPA | Sprague-Dawley rats | NC (most doses) | ↑ (high dose only) | NC | N/A | [48] |
| JNJ-10397049 | Sprague-Dawley rats | N/R | ↑ | NC | N/A | [74] |
| MK-1064 | Wild-type and HCRTR1; HCRTR2 DKO mice, Sprague-Dawley rats, and beagles | ↓ | ↑ | NC in mice; ↑ in rat | NR in DKO mice; NC in beagles | [84] |
| MK-3697 | Mouse, rat, and dog | ↓ | ↑ | ↑ | N/A | [75] |
| MK-8133 | Mouse, rat, and dog | ↓ | ↑ | ↑ in rat only | N/A | [92] |
| Seltorexant (JNJ-42847922/MIN-202) | Sprague-Dawley rats, C57BL6 and OX2R KO mice | N/R | ↑ | NC | N/R | [73] |
HCRT, hypocretin; HCRTR, hypocretin receptor; KO, knockout; N/A, not applicable; NC, no change; N/R, not reported; NREM, non-rapid-eye movement; REM, rapid-eye-movement.