Preparation and in vitro pharmacology of 5-HT4 receptor ligands. Partial agonism and antagonism of metoclopramide analogous benzoic esters

Article abstract of DOI:10.1002/ardp.19953280705

Alicyclic ester analogues of the gastroprokinetic benzamide metoclopramide (1) and its ester congener SDZ 205557 (2), a 5-HT₄ receptor antagonist, were prepared by O-alkylation of 4-amino-5-chloro-2-methoxybenzoate with N-(2-chloroethyl) substituted alicyclic amines. The bromo and iodo analogue of compound 13b (2-(1-piperidinyl)ethyl 4-amino-5-chloro-2-methoxybenzoate) were obtained by halogenation of dechloro-13b with N-halogenated succinimides. The series was evaluated in functional in vitro assays with regard to affinity for serotoninergic 5-HT₄, 5-HT₃ and muscarinic M₃ receptors. The affinities for 5-HT₃ and M₃ receptors were below 6.0 (pK(B) or pA₂). On 5-HT₄ receptors in guinea-pig ileal longitudinal muscle and rat oesophagus, the majority of compounds revealed partial 5-HT₄ receptor agonism susceptible to blockade by SDZ 205557, a reference 5-HT₄ receptor antagonist (pK(B) = 7.25-7.73 (guinea-pig ileum) and 7.09-7.43 (rat oesophagus)). The relative agonist potency was in the range of 5-303% (5-HT: 100%). Compound 13b and its bromo analogue 17 were the most potent esters of the series. The enantiomers of 13g ((R)- and (S)-2-(2-methyl-1-piperidinyl)ethyl 4-amino-5-chloro-2-methoxybenzoate) interacted stereoselectively with 5-HT₄ receptors and displayed enantiomeric potency ratios (R)/(S) of 4.3-8.7. There was an excellent correlation between (a) antagonist affinity on guinea-pig ileum and rat oesophagus, (b) relative agonist potency on guinea-pig ileum and rat oesophagus, and (c) between antagonist affinity and relative agonist potency within each assay (r² > 0.91). The new compounds may serve as academic tools in evaluating the functional role of 5-HT₄ receptors. The selective partial 5-HT₄ receptor agonists presented in this paper may be useful to restore physiological motility and secretion in the gut with reduced or absent propensity to elicit tachycardia and desensitization of the intestinal target receptor.