Activity of peptide and non-peptide antagonists at peripheral NK 1 receptors

Abstract

We investigated the affinity of several tachykinin antagonists reportedly selective for NK 1 receptors at various tachykinin receptors and NK 2 receptors subtypes. The four antagonists tested were: L 668,169, Spantide II, Ac-Thr-DTrp(for)-Phe-NMeBzl (FR 113680) and the novel nonpeptide antagonist (±)- CP-96,345. The four antagonists were found to be effective against NK 1 receptor-mediated responses in the guinea-pig ileum with the following rank order of potency (pK B values in parentheses): (±)-CP-96,345 (8.11) > Spantide II (7.08) > FR 113680 (6.61) ⩾ L 558,169 (6.44). (±)-CP-96,345, Spantide II and FR 113680 were distincly more potent at NK 1 receptors than at NK 2 receptors (NK 2A in the rabbit pulmonary artery, NK 2B in the hamster trachea). L 668,169 antagonized neurokinin A-induced contractions in the hamster trachea with an affinity similar (pK B value 6.16) to that found in the guinea-pig ileum for NK 1 receptors (pK B value 6.44). All antagonists were inactive at NK 3 receptors of the rat portal vein. In a second series of experiments, the affinities of test antagonists for NK 1 receptors in the guinea-pig ileum were compared to those for NK 1 receptors in the guinea-pig vas deferens, the rabbit jugular vein and the rat urinary bladder. For each antagonist, the affinity measured in the guinea-pig vas deferens and the rabbit jugular vein was comparable to that found in the guinea-pig ileum. In the rat urinary bladder, (±)-CP-96,345 was about 100 times less potent in blocking NK 1 receptor-mediated contractions than in the guinea-pig ileum. Spantide II, FR 113680 and L 668,169 were inactive in the rat urinary bladder in all concentrations tested. The results are discussed on the basis of the proposed existence of species-related subtypes of NK 1 receptors.