Interaction of valerian extracts of different polarity with adenosine receptors: Identification of isovaltrate as an inverse agonist at A1 receptors

A series of extracts of valerian roots (Valeriana officinalis L.) was prepared with solvents of different polarity. Polar as well as nonpolar extracts were found to interact with adenosine A1 receptors. While polar extracts activated A1 receptors (partial agonistic activity), nonpolar extracts showed antagonistic or inverse agonistic activity at A1 receptors, as demonstrated by GTPγS binding assays at human recombinant A1 receptors stably expressed in Chinese hamster ovary (CHO) cells. Guided by radioligand binding assays, fractionation of a lipophilic petroleum ether:diethyl ether (1:1) extract led to the isolation of isovaltrate, which was characterized as a potent, highly efficacious inverse agonist at adenosine A1 receptors (Ki rat A1: 2.05 μM). In experiments at rat brain slices measuring post-synaptic potentials (PSPs) in cortical neurons, isovaltrate at least partly reversed the reduction in the PSPs induced by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA). Isovaltrate may serve as a new lead structure for the development of inverse agonists at adenosine A1 receptors. The common use of hydrophilic, but not lipophilic valerian extracts as mild sleep-inducing agents is consistent with the opposite actions of hydrophilic and lipophilic extracts on adenosine receptors.