Novel H 2 S-Releasing Bifunctional Antihistamine Molecules with Improved Antipruritic and Reduced Sedative Actions.

Hydrogen sulfide (H 2 S) is an endogenous gasotransmitter with anti-inflammatory actions that also reduces itching. To test whether a combination of an antihistamine with a H 2 S donor has improved antipruritic efficacy, bifunctional molecules with antihistamine and H 2 S-releasing pharmacophores were synthesized and tested in vitro and in vivo . H 2 S release from the hybrid molecules was evaluated with the methylene blue and lead acetate methods, and H1-blocking activity was assessed by determining tissue factor expression inhibition. All new compounds released H 2 S in a dose-dependent manner and retained histamine blocking activity. Two compounds with the highest potency were evaluated in vivo for their antipruritic as well as sedative action; they proved to possess higher efficacy in inhibiting histamine-induced pruritus and decreased sedative effects compared to the parent compounds (hydroxyzine and cetirizine), suggesting that they exhibit superior antipruritic action and limited side effects that likely arise from the H 2 S-releasing moiety.