Metoclopramide analogues

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

Table 7.1. ANTAGONISM OF CISPLATIN-INDUCED EMESIS BY 2-SUBSTITUTED ANALOGUES (3) OF METOCLOPRAMIDE...

Modification of the basic side-chain of metoclopramide has been the subject of numerous investigations. Earlier work led to the synthesis of YM 09151-2 (15a) [8], clebopride (15b) [9], dazopride (15c) [10] and cisapride (15d) [11]. Modification of the basic side-chain and aromatic ring substitution led to the synthesis of alizapride (4a) [5], sulpiride (16a) [ 12] and cinitapride (16b) [13]. Although a number of analogues have found clinical use for various indications,... 

ML 10302 (RS 70678) is a substituted benzamide and analogue of metoclopramide, and is a (5-HT4-subtype) -HYDROXYTRYPTAMINE RECEPTOR AGONIST. 

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