Synthesis, biological activity, and conformational analysis of [pGlu 6 , N‐MePhe 8 , Aib 9 ] substance P (6–11): A selective agonist for the NK‐3 receptor

A highly potent and selective agonist to the tachykinin NK‐3 receptor, [pGlu 6 , N‐MePhe 8 , Aib 9 ] substance P (6–11) ( I ), was synthesized via the solid phase method. The ED 50 of I was 4n M in the guinea pig ileum in the absence of atropine (NK‐1 + NK‐3 receptors) and this agonist was 5000‐fold less potent in the presence of atropine (NK‐1 receptor). The analogue was virtually inactive in the rat vas deferens (NK‐2 receptor). A detailed analysis of the solution conformation of this analogue in DMSO‐d 6 and in a DMSO‐d 6 H 2 O cryornixture was carried out by a combination of 1 H‐nmr 2D techniques (DQF‐COSY, TOCSY, NOESY and ROESY) and model building based on empirical energy calculations. Peptide I exists as a mixture of isomers containing cis and trans Phe‐N‐MePhe peptide bonds. The main isomer, containing a cis Phe‐N‐MePhe peptide bond, shows a preferred folded conformation characterized by a type VI β‐turn with Phe and N‐MePhe in the i + 1 and i + 2 positions. The turn is followed by a helical segment extending to the C‐terminal. This conformation is compared to previously reported conformations of other selective tachykinin agonists and may be a promising lead for the design of novel NK‐3 agonists with additional conformational constraints. © 1993 John Wiley & Sons, Inc.