GM-109 - A NOVEL, SELECTIVE MOTILIN RECEPTOR ANTAGONIST IN THE SMOOTH-MUSCLE OF THE RABBIT SMALL-INTESTINE

The pharmacological properties of the cyclic peptide Phe-cyclo[Lys-Tyr (3-tBu)-beta Ala-] trifluoroacetate (GM-109), a selective motilin anta gonist, were investigated in the smooth muscle of the rabbit small int estine. GM-109 (0.1-3 mu M) competitively inhibited contractions induc ed by porcine motilin (pMTL) in rabbit isolated duodenum longitudinal strips, with a pA(2) value of 7.37 +/- 0.24. However, the contractile response to acetylcholine, to substance P, to prostaglandin F-2 alpha and to KCl was unaffected by 10 mu M GM-109 in the same preparation. B oth GM-109 and pMTL competitively inhibited I-125-pMTL binding to moti lin receptors in a homogenate of the rabbit small intestinal smooth mu scle tissue. The pK(i) value of GM-109 and the pK(d) value of unlabele d pMTL were 7.99 +/- 0.04 and 9.25 +/- 0.06 (each n = 5), respectively . These results indicate that GM-109 is a selective and competitive mo tilin receptor antagonist in the smooth muscle of the rabbit small int estine. Thus this compound may be a useful pharmacological tool for ex amining the functional role(s) of motilin.