Effect of several bicyclic peptide and cyclic pseudopeptide tachykinin NK2 receptor antagonists in the human isolated ileum and colon.

The affinities of the monocyclic pseudopeptides MEN10,508, MEN10,573, MEN10,581, MEN10,612, MEN10,619 and MEN10,677, and the bicyclic peptides MEN10,627, MEN10,692, MEN10,771, MEN10,882 and MEN10,993 were evaluated at the tachykinin NK2 receptors of the human isolated ileum and colon circular muscle preparations, by using [betaAla8]neurokinin A(4-10) as an agonist. All of the antagonists tested produced a concentration-dependent and competitive antagonism of [betaAla8]neurokinin A(4-10)-mediated contractions in both preparations. MEN10,612 (pKB = 8.1) and MEN10,627 (pKB = 8.4-8.8) were among the most potent analogs within their chemical classes. In general, the bicyclic peptide antagonists were more potent than the monocyclic peptide compounds, showing a nanomolar affinity for the human NK2 receptor. By comparing the affinities shown by the antagonists under study at NK2 receptors of the human gut with the affinities measured at NK2 receptors of the rabbit isolated pulmonary artery and hamster isolated trachea, a high degree of pharmacological homology was found between human and rabbit NK2 receptors. The present results point out the class of NK2 receptor antagonists bearing a bicyclic peptide structure, like MEN10,627, as candidates for testing in pathological conditions characterized by exaggerated gut motility, in which tachykinins might play a role as non-cholinergic excitatory neurotransmitters.