Senn Roman, Schertler Lukas, Bussmann Hendrik, Drewe Juergen, Boonen Georg, Butterweck Veronika
Analytical Department, Max Zeller & Soehne AG, Seeblickstrasse 4, 8590 Romanshorn, Switzerland.
Medical Department, Max Zeller & Soehne AG, Seeblickstrasse 4, 8590 Romanshorn, Switzerland.
Molecules. 2025 May 27;30(11):2344. doi: 10.3390/molecules30112344.
Valerian root extracts are widely used as mild sedatives to promote sleep, with clinical studies confirming their efficacy. Their sleep-promoting effects are associated with the adenosine A1 receptor (A1AR), a key regulator of sleep through neural activity inhibition. Adenosine, a neuromodulator that accumulates during wakefulness, activates A1ARs to facilitate sleep transitions. Using advanced analytics, we detected adenosine at 0.05% in the valerian extract Ze 911, supporting direct A1AR activation in vitro. Additionally, we explored A1ARs' allosteric sites for modulatory activity. Valerenic acid and pinoresinol, key constituents of Ze 911, were identified as positive allosteric modulators (PAMs) of A1ARs. Valerenic acid exhibited strong PAM activity, with high cooperativity ( = 4.79 for adenosine and = 23.38 for CPA) and intrinsic efficacy ( = 5.98 for adenosine and = 3.14 for CPA). Pinoresinol displayed weaker PAM activity, with moderate cooperativity ( = 3.42 for adenosine and = 0.79 for CPA) and limited efficacy ( = 0.93 for adenosine and = 1.66 for CPA). The allosteric modulation observed in valerian extract Ze 911 suggests a mechanism of action in which valerenic acid and pinoresinol enhance receptor activation through allosteric interactions, potentially amplifying the effects of endogenous adenosine. By targeting A1ARs' allosteric sites, valerian extract Ze 911 offers increased therapeutic selectivity and reduced off-target effects, emphasizing its potential for managing sleep disorders.
缬草根提取物被广泛用作温和的镇静剂来促进睡眠，临床研究证实了其有效性。它们的促睡眠作用与腺苷A1受体（A1AR）有关，A1AR是通过抑制神经活动来调节睡眠的关键因子。腺苷是一种在清醒期间积累的神经调质，它激活A1AR以促进睡眠转换。通过先进的分析方法，我们在缬草提取物Ze 911中检测到0.05%的腺苷，这支持了其在体外直接激活A1AR。此外，我们还探索了A1AR的变构位点的调节活性。缬草烯酸和松脂醇是Ze 911的关键成分，它们被鉴定为A1AR的正变构调节剂（PAM）。缬草烯酸表现出很强的PAM活性，具有高协同性（腺苷的协同性为4.79，CPA的协同性为23.38）和内在活性（腺苷的内在活性为5.98，CPA的内在活性为3.14）。松脂醇的PAM活性较弱，具有中等协同性（腺苷的协同性为3.42，CPA的协同性为0.79）和有限的活性（腺苷的活性为0.93，CPA的活性为1.66）。在缬草提取物Ze 911中观察到的变构调节表明了一种作用机制，即缬草烯酸和松脂醇通过变构相互作用增强受体激活，可能放大内源性腺苷的作用。通过靶向A1AR的变构位点，缬草提取物Ze 911具有更高的治疗选择性和更低的脱靶效应，强调了其在治疗睡眠障碍方面的潜力。
