title: Highly potent and selective heptapeptide antagonists of the neurokinin NK-2 receptor.
abstract: Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-Trp9 by D-Pro9 in the nonselective neurokinin antagonist [Arg5,D-Trp7,9, Nle11]-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Pro10 provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 4; NK-2 pKB = 5.9; NK-1 pKB = 4.7; NK-3 pKB less than 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 pKB = 8.2), and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 34, GR 94800; NK-2 pKB = 9.6; NK-1 pKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Group Research Ltd., Greenford, Middlesex, England.
authors.forename: A B
authors.initials: AB
authors.lastname: McElroy
authors.forename: S P
authors.initials: SP
authors.lastname: Clegg
authors.forename: M J
authors.initials: MJ
authors.lastname: Deal
authors.forename: G B
authors.initials: GB
authors.lastname: Ewan
authors.forename: R M
authors.initials: RM
authors.lastname: Hagan
authors.forename: S J
authors.initials: SJ
authors.lastname: Ireland
authors.forename: C C
authors.initials: CC
authors.lastname: Jordan
authors.forename: B
authors.initials: B
authors.lastname: Porter
authors.forename: B C
authors.initials: BC
authors.lastname: Ross
authors.forename: P
authors.initials: P
authors.lastname: Ward
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015288:Neurokinin A