Alpha-adrenergic receptors are cell membrane receptors encoded by six genes (a1A, a1B, a1D, a2A, a2B and a2C). The α1-adrenergic receptor is coupled to phospholipase C via Gq/11, and activation of the receptor results in the production of inositol trisphosphate (IP3) and diacylglycerol, which increases intracellular Ca2+ and activates protein kinases such as PKC. α2-adrenergic receptors negatively couple to adenylyl cyclase via Gi/o to lower cAMP. Activation of α2A-adrenergic receptors inhibits neurotransmitter release. Studies have shown that α2- and α1-adrenergic receptor proteins are expressed in human nasal mucosa. And α2-adrenergic receptors mediate vasoconstriction in pig and human nasal mucosa. Nasal obstruction associated with acute or allergic rhinitis may be due to increased nasal microvascular permeability due to cavernous plexus expansion and mucosal congestion. Therefore, exposure to simulated sympathetic vasoconstrictors causes the vascular smooth muscles of the nasal mucosa to contract, which can effectively treat nasal congestion. Here is a nasal decongestant spray, Xylometazoline, which shrinks nasal blood vessels and increases nasal airflow.

Xylometazoline is a high-affinity agonist of α-adrenergic receptors, mediating of smooth muscle contraction.

Firstly, Xylometazoline shows high affinity to most α-adrenergic receptor subtypes. While the order of mRNA levels of α-adrenergic receptor subtypes in human nasal mucosa is: α2A>α1A≥α2B>α1D≥α2C>>α1B, shows binding affinity Ki values of 0.88 μM, 0.05 μM, 1.7 μM, 0.15 μM, 0.19 μM, and 0.30 μM, respectively. Significantly, Xylometazoline behaves as a full agonist at α2B-adrenergic receptors and induces Ca2+ responses in cells heterologously expressing human α1A-adrenergic receptors. Therefore, Xylometazoline has an effective agonistic effect on α1/2-adrenergic receptors and can quickly and effectively relieve nasal congestion. Moreover, Xylometazoline also does not cause the sympathomimetic side effects common with oral decongestants (e.g., pseudoephedrine, phenylephrine).

In summary, Xylometazoline is a potent high-affinity agonist of α-adrenergic receptors. And also, it mediates mucosal vascular smooth muscle contraction and improves nasal congestion by inducing Ca2+ response.


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