Pharmacological properties of peptides derived from an antibody against the tachykinin NK1 receptor for the neuropeptide substance P.
Two peptides were derived from the structural analysis of a previously described monoclonal antibody [Mol. Immunol. 37 (2000) 423] against the tachykinin NK(1) receptor for the neuropeptide substance P. Here we show that these two peptides were able to inhibit the inositol phosphate transduction pathway triggered both by substance P and neurokinin A, another high-affinity endogenous ligand for the tachykinin NK(1) receptor. They also reduced the cAMP production induced by substance P. By contrast, only one antagonist peptide was able to prevent substance P and neurokinin A from binding the receptor, as revealed both by biochemical and autoradiographic studies. First, these results illustrate the generality of the antibody-based strategy for developing new bioactive peptides. Second, they indicate that antagonists, even exhibiting very close amino acid composition, can interact with the tachykinin NK(1) receptor at different contact sites, some of them clearly distinct from the contact domains for endogenous agonists.
Wijkhuisen
Anne
A
CEA, Service de Pharmacologie et d'Immunologie, DSV/DRM, Bât. 136, Centre d'Etudes de Saclay, 91191 Cedex, Gif-sur-Yvette, France.
Tymciu
Sylvie
S
Fischer
Jacqueline
J
Alexandrenne
Coralie
C
Créminon
Christophe
C
Frobert
Yveline
Y
Grassi
Jacques
J
Boquet
Didier
D
Conrath
Marie
M
Couraud
Jean-Yves
JY
D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001345:Autoradiography; D002417:Cattle; D022801:Complementarity Determining Regions / Q000096:biosynthesis* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000493:pharmacokinetics; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D010452:Peptide Biosynthesis; D010446:Peptide Fragments / Q000096:biosynthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
D022801:Complementarity Determining Regions; D007295:Inositol Phosphates; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D013373:Substance P; D015288:Neurokinin A; D000242:Cyclic AMP