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 peptid es MEN10,627, MEN10,692, MEN10,771, MEN10,882 and MEN10,993 were evalu ated at the tachykinin NK2 receptors of the human Isolated ileum and c olon circular muscle preparations, by using [beta Ala(8)]neurokinin A( 4-10) as an agonist. All of the antagonists tested produced a concentr ation-dependent and competitive antagonism of [beta Ala(8)]neurokinin A(4-10)-mediated contractions in both preparations. MEN10,612 (pK(B) = 8.1) and MEN10,627 (pK(B) = 8.4-8.8) were among the most potent analo gs within their chemical classes. In general, the bicyclic peptide ant agonists were more potent than the monocyclic peptide compounds, showi ng a nanomolar affinity for the human NK2 receptor. By comparing the a ffinities 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 re ceptors. The present results point out the class of NK2 receptor antag onists bearing a bicyclic peptide structure, like MEN10,627, as candid ates for testing in pathological conditions characterized by exaggerat ed gut motility, in which tachykinins might play a role as non-choline rgic excitatory neurotransmitters.