[Pro9]SP and [pGlu6, Pro9]SP(6-11) interact with two different receptors in the guinea-pig ileum as demonstrated with new SP antagonists.

Abstract Structural considerations led us to postulate that the introduction of the dipeptides DPro 9 -Pro 10 and DPro 9 -MeLeu 10 should lock the C-terminal tetrapeptide of SP in a type II' β-turn structure, a prerequisite for antagonist activity. Indeed, as the GR 71251, [DPro 9 , Pro 10 , Trp 11 ]SP was more potent in inhibiting the septide, (pA 2 = 6.5), than the [Pro 9 ]SP, (pA 2 ≤ 5), spasmogenic activity in the guinea-pig ileum bioassay. This result confirms that septide, [pGlu 6 , Pro 9 ]SP(6–11), a peptide active in the guinea-pig ileum bioassay and practically devoid of binding potencies for the three specific NK-1, NK-2 and NK-3 tachykinin binding sites interacts with a tachykinin receptor different from the NK-1 receptor sensitive to [Pro 9 ]SP. Interestingly enough, the reintroduction of the leucine side-chain in position 10 yielded [DPro 9 , MeLeu 10 , Trp 11 ]SP, an antagonist, equipotent in inhibiting both the septide- and the [Pro 9 ]SP-evoked contractile response in the guinea-pig ileum bioassay, (pA 2 = 6.6).