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.

Related Papers

• → Characterization of the binding of [125I-iodo-histidyl,methyl-Phe7] neurokinin B to the neurokinin-3 receptor(1993)31 cited
• → Expression of two different tachykinin receptors in Xenopus oocytes by exogenous mRNAs(1987)63 cited
• → Effects of receptor‐selective neurokinin agonists and a neurokinin antagonist on the electrical activity of spinal cord neurones in culture(1989)5 cited
• → [D-Pro2,D-Trp6,8,Nle10]-Neurokinin B: Pharmacological Profile of a Novel Neurokinin Antagonist(1987)3 cited
• → Evidence for Three Distinct Peripheral Neurokinin Receptors Using a Putative Neurokinin B Antagonist(1987)1 cited