SYNTHESIS OF A POTENT ANTAGONIST OF SUBSTANCE-P BY REPLACING THE CH2SCH3 AND THE ALPHA-CARBOXAMIDE GROUPS OF THE METHIONINE AT [ORN6]-SP(6-11) BY BENZYL ESTER GROUPS

Analogues of [Orn6]-SP6-11 have been synthesized in which the CH2SCH3 group of Met11 is replaced by a COOCH3 or a COOBzl group. These analog ues, which were tested for agonist and antagonist activity in three in vitro preparations representative of NK- 1, NK-2 and NK-3 receptor ty pes, were full agonists at NK-1 receptors, showed very weak agonist ac tivity at NK-2 receptors and were weak antagonists at NK-3 receptors. The above analogues were modified by substituting the alpha-carboxamid e of residue 11 by a COOCH3 and a COOBzl group, respectively. The resu lting analogues were found to be devoid of agonist activity in each of the functional assays. However, they showed weak antagonist activity at each receptor subtype, with the exception of the dibenzyl analogue, which was a potent and selective NK-1 receptor antagonist. It is conc luded that appropriate modification of the side chain of Met11 and its alpha-carboxamide leads to a potent and selective at NK-1 receptor an tagonist. (C) Munksgaard 1993.