A Role for Histamine and Substance P in Immediate Allergic Responses in Guinea Pig Airways: Characterization of MDL 108,207DA, a Dual H₁ / NK-1 Receptor Antagonist

Abstract

Background: Histamine is a critical mediator of immediate hypersensitivity reactions. Sensory neuropeptides, such as substance P (SP), may also contribute to acute inflammatory responses. A compound which antagonizes both H₁ and NK-1 receptors, such as MDL 108,207DA, may present a significant therapeutic advantage over pure antihistamines. Methods: The binding affinity of MDL 108,207DA for H₁ and NK-1 receptors was evaluated and its potency of antagonism evaluated in vitro. The in vivo antagonism of SP- or histamine-induced microvascular leakage in guinea pig airways was examined. A role for these mediators in antigen-induced microvascular leakage in ovalbumin-sensitized guinea pig airways was examined using MDL 108,207DA as well as the NK-1-selective antagonist FK888 and the H₁-selective antagonist pyrilamine alone or in combination. Results: The affinity of MDL 108,207DA for H₁ and NK-1 receptors is similar to that of receptor-selective antagonists. The compound inhibits both receptors in vitro and in vivo with comparable potencies for each. The efficacy of FK888 in combination with pyrilamine and MDL 108,207DA on antigen-induced microvascular leakage in sensitized guinea pig airways supports a role for both SP and histamine in early allergic responses. Conclusion: The contribution of both SP and histamine to immediate hypersensitivity reactions supports the utility of NK-1 and H₁ receptor antagonist therapy. MDL 108,207DA incorporates both activities into the same compound and, as a result, may be useful in the treatment of allergic diseases.

Antibodies directed against nerve growth factor inhibit the acute bronchoconstriction due to allergen challenge in guinea‐pigs

“…Few studies are published on the involvement of tachykinins in acute allergic responses in the airways. Antigen‐induced microvascular leakage revealed a role for substance P in the early allergic response [28]. Recently it was shown that toluene diisocyanate induces a rapid increase of substance P; 1 h after inhalation of toluene diisocyanate the number of substance P immuno‐reactive nerve fibres was already increased [29].…”

Evaluation of Urtica dioica Phytochemicals against Therapeutic Targets of Allergic Rhinitis Using Computational Studies

“…The existence of phytochemicals with a high affinity for more than one pharmacological target presents a great advantage. Multiple reports highlight the benefits of combining therapies for AR treatment [44], such as the inhibition of HR1 and NKR1 [45] or HR1 and CLR1 [46]. Therefore, we performed MD simulations to further analyze the ability of amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside to function as antagonists of the five selected targets.…”