Design and Synthesis of Effective Antagonists of Substance P.

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Abstract
The agonist/antagonist activities of 4 background analogs of substance P (SP) facilitated design and synthesis of 12 new analogs to achieve effective antagonists. (D-Pro2,D-Phe7,D-Trp9)-SP,(D-Pro2,D-Trp7,9)-SP and (D-Arg1,D-Phe7,D-Trp9)-SP showed no agonist activity; 9 analogs showed weak agonist activity of SP in guinea pig ileum. (D-Pro2,D-Trp7,9)-SP was the most potent antagonist, which at a concentration of 10-5 required a 3-fold increase in SP to allow a 50% response by SP. (D-Pro2,Lys6,D-Phe7)-SP and (D-Pro2,D-pClPhe7,D-Trp9)-SP were also potent, and the antagonism was competitive. For specific pairs of peptides Lys6 is a promising substituent. D-Trp7,9 was as effective as Lys6,D-Phe7. D-pClPhe7 was 3 times as effective as D-Phe7. D-Dln6 was 1.33-fold better than D-Gln5. D-Pro2 and D-Pro4 were equally effective. D-Pro2 was 1.5 times as effective as D-Lys3. D-Pro2 may not be important. D-pClPhe and D-Trp9 were equally effective.

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