[pGlu⁶,Pro⁹]SP_6-11, a Selective Agonist for the Substance P P-Receptor Subtype

Substitution of a single amino acid residue, proline for glycine-9 in [pGlu⁶]SP_6-11, a hexapeptide analogue of substance P, confers on the peptide selective agonist activity toward the SP-P receptor.subtype. [pGlu⁶,Pro⁹]SP_6-11 had 20% and 75% of the activity of [pGlu⁶]SP_6-11in stimulating, respectively, K₊ release from rat parotid slices and contraction of the isolated guinea pig ileum, via the SP-P receptor subtype. In contrast, [pGlu⁶,Pro⁹]SP_6-11 had substantially reduced activity on SP-E systems such as the hamster urinary bladder and rat duodenum, being about 20-fold less potent than [pGlu₆]Sp_6-11 and 200-670-fold less potent than neurokinin B. In the guinea pig ileum [pGlu⁶,Pro⁹]SP_6-11 had very low activity on the neuronal tachykinin receptor, being 325 times less potent than [pGlu⁶]Sp_6-11and 1000 times less potent than neurokinin B. Because of its discrimination between the muscular and neuronal receptors in the guinea pig ileum (muscular/neuronal potency ratio = 600), [pGlu⁶,Pro⁹]SP_6-11 can be used to specifically desensitize the muscular receptor of this tissue. This procedure enables a selective and sensitive bioassay of the neuronal receptor.