Mixed carboxylic‐phosphinic anhydrides derived from peptide acids and 1‐oxo‐1‐chlorophospholane have been applied in the synthesis of the protected [Leu11]‐SP1‐11 by the fragment coupling strategy. The yields from fragment couplings were ca. 75%, the products were of high purity while the conditions of formation and coupling of the corresponding mixed phosphinic anhydrides, for optimum yields, have been evaluated.

Analogues of [Orn6]‐SP6‐11 have been synthesized in which the Met11 residue is replaced by glutamate γ‐alkylesters. These analogues were tested in three in vitro preparations representative of NK‐1, NK‐2, and NK‐3 receptor types. Substitution of the SCH3 group of the Met11 side chain by a COOR (R = methyl, ethyl, n‐propyl, n‐butyl, cyclohexyl) group results in analogues which are full agonsists in NK‐1 and NK‐2 preparations but show little agonist activity in the NK‐3 preparation. When the SCH3 group is replaced by a t‐butyl ester group and the resulting analogue is a full agonist in all the above preparations and more active than the parent hexapeptide and SP‐OCH3 at NK‐1 receptors. It is concluded that for activity at NK‐1 receptors methionine can be replaced by γ‐t‐butyl glutamate without loss of activity, whilst at NK‐2 and NK‐3 receptors the above substitution increases the activity of [Orn6]‐SP6‐11. Other γ‐alkyl esters of the glutamic acid reduce its biological activity.

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Analogues of [Orn6]‐SP6–11 have been synthesized in which the Met11‐NH2 residue is replaced by the α,γ‐dimethyl, α,γ‐dibenzyl and α,γ‐di‐tert‐butyl esters of glutamic acid. These analogues were tested in three in vitro preparations representative of NK‐1, NK‐2 and NK‐3 receptor types for agonist and antagonist activity. The dimethyl analogue is a selective full agonist in the NK‐1 receptor type and a weak antagonist in the other two receptor types, while the dibenzyl and the di‐tert‐butyl analogues are potent antagonists in the NK‐1 receptor type and weak antagonists in the other two receptor types. It is concluded that appropriate modification at the α‐carboxamide and the side chain of the methionine residue of substance P may induce antagonism without using d‐amino acids.

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