SPANTIDE-II, AN EFFECTIVE TACHYKININ ANTAGONIST HAVING HIGH POTENCY AND NEGLIGIBLE NEUROTOXICITY

Spantide (D-Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-D-Trp7-Phe8-D-Trp9-Leu10-L eu11-NH2) was introduced as a tachykinin antagonist in 1984 and has served as a starting point in the design of new antagonists that have proven to be more effective and have exhibited no neurological side effects. The most remarkable and unpredictable structural change that significantly increased potency was deletion of a methylene group by changing Gln6 to Asn6. On the basis that D-Arg1 and Lys3 of spantide contribute to neurological side effects, many new designs led to D-Lys(Nic)1-Pro2-Pal(3)3-Pro4-D-Phe(Cl2)5-Asn6-D-Trp7-Phe8-D- Trp9-Leu10-Nle11-NH2 [spantide II, where D-Lys(Nic) is N(ε)-nicotinoyllysine, Pal(3) is 3-(3-pyridyl)alanine, D-Phe(Cl2) is 3,4-dichloro-D-phenylalanine, and Nle is norleucine], which is a potent antagonist without neurotoxicity. Spantide II, an undecapeptide, has a total of seven substitutions in the sequence of substance P, consisting of two natural L amino acids, and one unnatural L amino acid, and four unnatural D amino acids. The π- and σ-bond amino acid substituents of substance P and spantide II are compared toward a future understanding of the essential substituents for mechanism and inhibition binding. Spantide II has five π-bond and six σ-bond amino acid moieties, and substance P has two π-bond and nine σ-bond moieties.