In vitro pharmacological profile of SK-896, a new human motilin analogue

SK-896 ([Leu(13)]motilin-Hse) is a new human motilin analogue synthesized b y Escherichia coli using a biotechnological method. We investigated the bin ding of SK-896 to motilin receptors and the contractile effect of SK-896 on smooth muscle preparations isolated from the gastrointestinal tract and va rious regional organs in order to clarify its in vitro pharmacological prof ile. SK-896 inhibited the binding of I-125-human motilin to rabbit gastrodu odenal motilin receptors with the same potency as unlabeled human motilin. The IC50 values of SK-896 and human motilin were 3.5 +/- 1.5 and 3.1 +/- 1. 8 nmol/l, respectively. The K-d of human motilin was 3.0 +/- 1.5 nmol/l, an d the Ki of SK-896 was 3.4 +/- 1.5 nmol/l. SK-896 induced contraction of sm ooth muscle preparations isolated from rabbit duodenum in a concentration-d ependent manner. However, there was no effect of SK-896 on duodenal prepara tions isolated from the dog and the rat. SK-896 thus exhibited species spec ificity in its contractile effect. We next investigated the effect of SK-89 6 on various smooth muscle preparations isolated from rabbit gastrointestin al tract, trachea, bladder, gallbladder, uterus, vas deferens and artery. R esults showed that SK-896 induced contraction of smooth muscle preparations isolated from gastrointestinal tract, with potencies in the order duodenum > gastric pylorus = jejunum = descending colon > ascending colon greater t han or equal to ileum. However, there was no effect of SK-896 on smooth mus cle preparations from gastric fundus and other regional organs. SK-896 thus exhibited regional specificity in its contractile effect. Moreover, the ef fects of SK-896 on smooth muscle preparations from rabbit duodenum were the same as those of human motilin, and were not inhibited by pretreatment wit h tetrodotoxin and atropine but were inhibited by verapamil. These findings indicate that SK-896 has the same pharmacological profile as human motilin . They suggest that SK-896 acts on gastrointestinal smooth muscle isolated from rabbit directly and specifically. Copyright (C) 2000 S. Karger AG, Bas el.