SPANTIDE-II, A NOVEL TACHYKININ ANTAGONIST HAVING HIGH POTENCY AND LOW HISTAMINE-RELEASING EFFECT

Two undecapeptide substance P (SP) analogues, Spantide I and Spantide II, were tested for their capacity to block the contractile effect of SP on the guinea pig isolated taenia coli and the contractile effect of electrical stimulation of the rabbit isolated (and atropinized) iris sphincter, and for their capacity to mobilize histamine from rat isolated peritoneal mast cells. Spantide I and Spantide II have one feature in common, namely d-tryptophan in positions 7 and 9. Spantide I: d-Arg, Pro2, Lys3, Pro4, Gln5, Gln6, D-Trp7, Phe8, d-Trp9, Leu10, Leu11-NH2. Spantide II: d-NicLys1, Pro2, 3-Pal3, Pro4, d-Cl2Phe5, Asn6, D-Trp7, Phe8, D-Trp9, Leu10, Nle11-NH2. Both Spantide I and II were found to be competitive antagonists to SP on the taenia coli and to be capable of blocking the electrically induced non-cholinergic contraction of the iris sphincter. Spantide II had higher pA2 value (taenia coli) than Spantide I, 7.7 versus 7.0, and higher pIC50 value (blockade of tachykinin-mediated neurotransmission in iris sphincter), 6.0 versus 5.1. Both Spantide I and II mobilized histamine from rat peritoneal mast cells but Spantide II was less effective. Spantide I and II were tested for antagonistic specificity. Both blocked contractions of the taenia induced by SP and neurokinin A. In the concentration used, Spantide II in addition blocked the response to neurokinin B. The contractions induced by carbachol, 5-hydroxytryptamine, histamine and prostaglandins (F2α and E1) were not affected; the contractile response to bombesin was inhibited by Spantide I but not by Spantide II. © 1990.