Center for Neuroscience and Metabolic Disease Research, SRI International, Menlo Park, California, USA.
PLoS One. 2012;7(7):e39131. doi: 10.1371/journal.pone.0039131. Epub 2012 Jul 2.
The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4-6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking "drive".
下丘脑泌素（食欲素）系统参与睡眠/觉醒调节，而下丘脑泌素受体 1（HCRTR1）和/或 HCRTR2 的拮抗剂被认为是有潜力的催眠药物。目前尚不清楚阻断这两种受体中的一种或两种是否更有效，同时还能将副作用降到最低。因此，我们比较了选择性 HCRTR1（SB-408124 和 SB-334867）和 HCRTR2（EMPA）拮抗剂与双重 HCRTR1/R2 拮抗剂阿莫雷克斯坦（almorexant）在大鼠体内的特性。所有 4 种拮抗剂在体外均与各自的受体具有高亲和力和选择性结合。由于体内药代动力学实验表明 SB-408124 脑穿透性差，因此选择 SB-334867 进行后续体内研究。当在中活跃期注射时，SB-334867 可使快速眼动（REM）和非快速眼动（NR）睡眠轻度增加。在研究的最高剂量下，EMPA 仅使 NR 显著增加。相反，almorexant 在随后的 6 小时内降低了 NR 潜伏期，并使 NR 和 REM 按比例增加，而没有出现清醒的反弹。增加的 NR 是由于 NR 发作次数的增加；NR 发作持续时间没有变化。在测试的最高剂量（100mg/kg）下，almorexant 通过增加觉醒和 REM 发作次数来破坏睡眠结构。没有观察到猝倒。almorexant 对 HCRTR1 的占据在给药后 4-6 小时下降，而 HCRTR2 的占据在 12 小时后仍升高，这揭示了 HCRT 受体的占据与促进睡眠之间的复杂关系。我们得出结论，与单独阻断 HCRTR1 相比，双重 HCRTR1/R2 阻断更有效地促进睡眠。与通过广泛抑制诱导睡眠的 GABA 受体激动剂不同，HCRTR 拮抗剂似乎通过减少清醒“驱动力”来促进睡眠。
