Increased potency of antagonists of substance P having asparagine in position 6

The general structure of antagonists of substance P (SP) which was found with the development of Spantide and analogs based on Spantide served for further refinement. The antagonistic potency was tested in vitro on guinea pig ileum and taenia coli. It was unexpectedly found that introduction of Asn 6 gave rise to a considerable increase in potency. The exchange of Gln 6 for Asn 6 entails the shortening of the side chain by one CH 2 unit and seems slight for steric advantages and potency increase. The analog [ d-Arg 1, d-Cl 2Phe 5,Asn 6, d-Trp 7,9,Nle 11]SP had pA 2 values of 7.4 (ileum) and 8.0 (taenia coli). We then used this sequence as a new lead to introduce new changes, which were made in positions 1, 3, 5, 7 and 9. It was found that Arg 1 is important, but Lys 3 can be exchanged. The Pal 3 derivative had p A 2 values of 8.1 and 8.0 and the Nle 3 counterpart had 7.7 and 7.4. d-Cl 2Phe is an effective substituent in position 5. d-Trp in positions 7 and 9 were superior to other alternatives.