Rational design of high affinity tachykinin NK1 receptor antagonists.
The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv.
Boyle
S
S
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, U.K.
Guard
S
S
Higginbottom
M
M
Horwell
D C
DC
Howson
W
W
McKnight
A T
AT
Martin
K
K
Pritchard
M C
MC
O'Toole
J
J
Raphy
J
J
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects
D001798:Blood Proteins; D064729:Neurokinin-1 Receptor Antagonists; D014364:Tryptophan; C089683:PD 154075