Effect of TZP-201, a novel motilin receptor antagonist, in the colon of the musk shrew (Suncus murinus).

OBJECTIVES: Motilin is the main gut peptide that stimulates propulsive motility in the upper gastrointestinal (GI) tract. Motilin receptors exist in the colon but little is known about their functional role, and species-dependent differences present a major obstacle to understanding the physiological significance and potential therapeutic implications of motilin receptors in the colon. Our study aimed to define whether a motilin receptor is functionally expressed in the colon of the Asian musk (or house) shrew (Suncus murinus) and to investigate the effect of a novel motilin receptor antagonist, TZP-201.

METHODS: GI tissue (gastric antrum, small intestine and colon) was isolated from male shrews and the effects of a motilin receptor agonist [Nle13]motilin and the antagonist TZP-201 on contractile activity and mucosal electrogenic transport of water and electrolytes were investigated in vitro.

KEY FINDINGS: [Nle13]motilin induced a moderate increase in spontaneous contractility in the stomach and no significant changes in the small intestine; a marked increase in contractility was found in the colon. Motilin-induced contractions in the colon were abolished by tetrodotoxin or atropine, and dose-dependently inhibited by 0.01-10 muM TZP-201. Neither [Nle13]motilin nor TZP-201 had any effect on basal mucosal transport.

CONCLUSIONS: Shrew colon expresses a functional motilin receptor that induces contractile activity by the activation of enteric cholinergic neurons. TZP-201 inhibited motilin-induced colonic contractions. Motilin antagonists may represent a new approach for the treatment of GI motility disorders characterised by hypercontractility.