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.
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.


CONCLUSIONS
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.
Kudlacz
E
E
Hoechst Marion Roussel, Cincinnati, Ohio 45215, USA.
Shatzer
S
S
Logan
D
D
Olsen
K
K
Knippenberg
R
R
Hsieh
L
L
Esteve
H
H
Maynard
G
G
D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001980:Bronchi / Q000098:blood supply; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects; D006224:Cricetinae; D004151:Dipeptides / Q000494:pharmacology; D004338:Drug Combinations; D006168:Guinea Pigs; D006632:Histamine / Q000502:physiology*; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010047:Ovalbumin; D011738:Pyrilamine / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D012882:Skin Tests; D013373:Substance P / Q000502:physiology*; D014132:Trachea / Q000098:blood supply; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D001562:Benzimidazoles; D004151:Dipeptides; D004338:Drug Combinations; D006634:Histamine H1 Antagonists; D007211:Indoles; D007295:Inositol Phosphates; C110516:MDL 108,207DA; D064729:Neurokinin-1 Receptor Antagonists; D011759:Pyrrolidines; D011969:Receptors, Histamine H1; D018040:Receptors, Neurokinin-1; C078949:FK 888; D013373:Substance P; D006632:Histamine; D010047:Ovalbumin; D011738:Pyrilamine