title: Rational design of high affinity tachykinin NK1 receptor antagonists.
abstract: 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.
authors.affiliation: Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, U.K.
authors.forename: S
authors.initials: S
authors.lastname: Boyle
authors.forename: S
authors.initials: S
authors.lastname: Guard
authors.forename: M
authors.initials: M
authors.lastname: Higginbottom
authors.forename: D C
authors.initials: DC
authors.lastname: Horwell
authors.forename: W
authors.initials: W
authors.lastname: Howson
authors.forename: A T
authors.initials: AT
authors.lastname: McKnight
authors.forename: K
authors.initials: K
authors.lastname: Martin
authors.forename: M C
authors.initials: MC
authors.lastname: Pritchard
authors.forename: J
authors.initials: J
authors.lastname: O'Toole
authors.forename: J
authors.initials: J
authors.lastname: Raphy
mesh_terms: 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
chemical_list: D001798:Blood Proteins; D064729:Neurokinin-1 Receptor Antagonists; D014364:Tryptophan; C089683:PD 154075