PHARMACOLOGICAL ASSESSMENT OF SPANTIDE-II ANALOGS

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.