title: In vitro pharmacological profile of SK-896, a new human motilin analogue.
abstract: SK-896 ([Leu(13)]motilin-Hse) is a new human motilin analogue synthesized by Escherichia coli using a biotechnological method. We investigated the binding of SK-896 to motilin receptors and the contractile effect of SK-896 on smooth muscle preparations isolated from the gastrointestinal tract and various regional organs in order to clarify its in vitro pharmacological profile. SK-896 inhibited the binding of (125)I-human motilin to rabbit gastroduodenal motilin receptors with the same potency as unlabeled human motilin. The IC(50) 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, and the Ki of SK-896 was 3.4 +/- 1.5 nmol/l. SK-896 induced contraction of smooth muscle preparations isolated from rabbit duodenum in a concentration-dependent manner. However, there was no effect of SK-896 on duodenal preparations isolated from the dog and the rat. SK-896 thus exhibited species specificity in its contractile effect. We next investigated the effect of SK-896 on various smooth muscle preparations isolated from rabbit gastrointestinal tract, trachea, bladder, gallbladder, uterus, vas deferens and artery. Results 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 >/= ileum. However, there was no effect of SK-896 on smooth muscle preparations from gastric fundus and other regional organs. SK-896 thus exhibited regional specificity in its contractile effect. Moreover, the effects of SK-896 on smooth muscle preparations from rabbit duodenum were the same as those of human motilin, and were not inhibited by pretreatment with 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.
authors.affiliation: Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan. k_tsukamoto@mb4.skk-net.com
authors.forename: K
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: N
authors.initials: N
authors.lastname: Kuboyama
authors.forename: M
authors.initials: M
authors.lastname: Yamano
authors.forename: T
authors.initials: T
authors.lastname: Nakazawa
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D009037:Motilin / Q000031:analogs & derivatives*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011964:Receptors, Gastrointestinal Hormone / Q000187:drug effects* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000187:drug effects* / Q000378:metabolism
chemical_list: D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin