Synthesis and biological activity of analogues of the C-terminal hexapeptide of substance P with modifications at glutaminyl and methioninyl residues

Analogues of [Orn⁶]-SP_6-11 have been synthesized in which the methionyl residue is replaced by glutamine γ-carboxamide substituted derivatives. These analogues where 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 CONHCH₃, CON(CH₃)₂, CONHPh and CONCH₃Ph groups results in analogues which are full agonists in NK-1 and NK-2 preparations with the exception of the Glu[N(CH₃)₂]¹¹ and the Glu(NHCH₃)¹¹ analogues, which are partial agonists at NK-1 and NK-2 receptors respectively. The Glu(NHCH₃)¹¹ analogue shows selectivity for the NK-1 receptor type and is equipotent to the Glu(NCH₃Ph)¹¹ analogue in the same receptor type. The latter analogue is 2.84 times more potent than the parent hexapeptide in the NK-2 preparation. The Glu(NHPh)¹¹ analogue is a full agonist in the NK-3 preparation and equipotent to the parent hexapeptide, in contrast to the other analogues in which Met has been replaced by glutamine γ-carboxamide substituted residues. It is concluded that for NK-1 receptor type the lipophilic character of Met¹¹ side chain is not a determining factor for activity but it is an important factor for activity in the NK-2 receptor type and has a stronger effect when a phenyl group is present, thus leading to analogues which are full agonists and more potent than the parent hexapeptide.