We have studied the structure-activity relationship of a series of tac
hykinin receptor antagonists based on spantide II. Fifteen novel pepti
des were tested for their ability to antagonize the electrically evoke
d tachykinin receptor-mediated response in the isolated rabbit iris sp
hincter muscle. Substitution or deletion of one to three amino acids i
n the spantide II sequence caused significant changes in biological ac
tivity. Eight of the novel analogues were found to be as potent as or
more potent than spantide II and some were found to have better water
solubility. We tested the selectivity for different tachykinin recepto
rs of spantide II and two of the eight most potent analogues. They all
interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin N
K2 (rabbit pulmonary artery) receptors with pA(2) values of about 6.5-
7.5 at the NK1 receptor and of 5.9-7.2 at the NK2 receptor, while bein
g inactive at the tachykinin NK3 receptor (rat portal vein). Spantide
II and the novel analogues were without effect on electrically evoked
cholinergic responses of the isolated rabbit iris sphincter and on ele
ctrically evoked sympathetic responses of the guinea-pig vas deferens;
moreover, they were without local anaesthetic-like effects on action
potentials of the frog sciatic nerve, which suggests that they do not
produce a general neurosuppressive effect. They were as effective as o
r slightly less effective than spantide II in causing histamine releas
e from rat peritoneal mast cells.