Structure‐Activity Relation of Erythromycin‐Related Macrolides in Inducing Contractions and in Displacing Bound Motilin in Rabbit Duodenum

Abstract

ERYTHROMYCIN A appears to be a motilin agonist, although motilin (a peptide) and erythromycin A (a 14‐member macrolide antibiotic carrying two sugar substituents) are structurally totally unrelated. To obtain information concerning the structural requirements for erythromycin's interaction with the motilin receptor, we studied 60 derivatives and seven fragments of erythromycin, and six macrolides with a 16‐member ring structure. For every compound the ability to displace motilin bound to a crude homogenate of rabbit antral smooth muscle tissue and the ability to induce contractions in rabbit duodenal segments were determined. For both parameters dose‐response curves were obtained, and the negative logarithms of the concentrations inhibiting 50% of the binding (pIC‐50) or inducing 50% of the maximum response to a maximal contractile dose of acetylcholine (pEC‐50) were determined. All macrolides with a 16‐member ring structure were inactive in both types of experiments. In all erythromycin derivatives variations of the ring structure had a marked effect. For both parameters the order of potency was enol ether > pseudo–enol ether > parent ring > pseudo‐hemiketal > anhydro. The two sugars attached to the ring were important too, because removing either or both of them resulted in an inactive compound. Modifications of the dimethylamino group of the desosamine sugar affect the potency, while the orientation of the cladinose moiety seems to be important too. For all active compounds, both parameters studied were well correlated (r= 0.80, p < 0.001). Our results support the concept that erythomycin‐like macrolides are motilin agonists. The structural requirements of these “motilides” involve the ring structure, especially the part that can be transformed into an enol ether, and both attached sugars. Potent derivatives may prove to be useful as gastrokinetic agents with a very specific target zone.