Identification of a critical residue in the transmembrane domain 2 of tachykinin neurokinin 3 receptor affecting the dissociation kinetics and antagonism mode of osanetant (SR 142801) and piperidine-based structures.
In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr139(2.58) in human, corresponding to Ala114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).
Malherbe
Pari
P
Discovery Research CNS, F. Hoffmann-La Roche Ltd., PRDN, Building 69/333, CH-4070 Basel, Switzerland. parichehr.malherbe@roche.com
Kratzeisen
Claudia
C
Marcuz
Anne
A
Zenner
Marie-Thérèse
MT
Nettekoven
Matthias H
MH
Ratni
Hasane
H
Wettstein
Joseph G
JG
Bissantz
Caterina
C
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007553:Isotope Labeling; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014316:Tritium / Q000737:chemistry
D007295:Inositol Phosphates; D010880:Piperidines; D018042:Receptors, Neurokinin-3; D014316:Tritium; C032727:piperidine; C091554:SR 142801