The non-peptide tachykinin NK2 receptor antagonist SR 48968 interacts with human, but not rat, cloned tachykinin NK3 receptors.
SR 48968, a non-peptide tachykinin NK2 receptor antagonist, has been shown to possess sub-micromolar affinity for NK3 receptors present in the guinea pig. In the present study, we have compared the binding affinities of SR 48968 to the cloned human and rat NK3 receptors expressed in CHO cells. Using [125I]-[MePhe7]-neurokinin B as the radioligand, SR48968 displayed an IC50 value of 350 nM for the human NK3 receptor as compared with a value of greater than 10 microM for the rat NK3 receptor. Exposure of cells transfected with human NK3 receptor cDNA to [Pro7]-neurokinin B increased inositol phospholipid turnover in a concentration-dependent manner and this response was blocked competitively by SR 48968. Our results demonstrate that SR 48968 is an antagonist at the human NK3 receptor and may be a useful tool for elucidating the species-dependent variations in the non-peptide antagonist binding site(s) on the NK3 receptor.
Chung
F Z
FZ
Department of Biotechnology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105-1047.
Wu
L H
LH
Vartanian
M A
MA
Watling
K J
KJ
Guard
S
S
Woodruff
G N
GN
Oxender
D L
DL
D000818:Animals; D001483:Base Sequence; D001549:Benzamides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D017931:DNA Primers; D005333:Fetus; D005813:Genes, Synthetic; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000378:metabolism*; D012333:RNA, Messenger / Q000302:isolation & purification / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015183:Restriction Mapping; D014162:Transfection
D001549:Benzamides; D017931:DNA Primers; D010880:Piperidines; D012333:RNA, Messenger; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D011994:Recombinant Proteins; C073839:SR 48968; D015288:Neurokinin A