The conformational space of two NK2 receptor agonists and a new potent antagonist has been sampled by the simulated annealing technique. Low-energy conformers were obtained, which were compared with respect to their key residues, namely phenylalanine, leueine and methionine. The hypothesis is that they share part of the binding site on the receptor. Mammalian tachykinins are peptide neurotransmitters which interact, with different affinities, with a class of G-protein-coupled receptors. The behaviour of the natural agonists differentiates these receptors as NK~, to which Substance P (SP) shows the highest affinity, and NK2 and NK3, which preferentially bind Neurokinin A and Neurokinin B, respectively. These receptors, particularly NK1 and NK2, are considered to be involved in pain transmission and in the so-called 'neurogenic inflammation' [1]. The amino acid sequences of the tachykinins are depicted in Scheme 1.
Although more potent at their own 'preferred' receptor, natural TKs are, at different concentrations, equally effective in stimulating the three receptor types. For this reason a number of receptor-selective synthetic agonists have been developed, each stimulating exclusively only one of the three receptor types. [I]-AlaS]NKA(4-10) [2] and GR-64349 [3] are two of the most potent synthetic NK 2 receptor agonists available.
Recently, a new potent NK 2 receptor antagonist has been discovered, the polycyclic peptide derivative MEN-10627 [4]. This peptide shares a feature common among compounds that are active as agonists on the NK2 receptor, i.e., the sequence leucine-methionine. With the purpose to gain some insight into the mechanism of action of this new class of peptides with respect to the NK 2 receptor agonists, we have performed a conformational comparison between MEN-10627 and the two agonists []3-AlaS]NKA(4-10) and GR-64349.