HIGHLY POTENT AND SELECTIVE HEPTAPEPTIDE ANTAGONISTS OF THE NEUROKININ NK-2 RECEPTOR

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 pK(B) = 5.9; NK-1 pK(B) = 4.7; NK-3 pK(B) < 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 pK(B) = 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 pK(B) = 9.6; NK-1 pK(B) = 6.4; NK-3 pK(B) = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.