PREPARATION AND IN-VITRO PHARMACOLOGY OF 5-HT4 RECEPTOR LIGANDS - PARTIAL AGONISM AND ANTAGONISM OF METOCLOPRAMIDE ANALOGOUS BENZOIC ESTERS

Alicyclic ester analogues of the gastroprokinetic benzamide metoclopra mide (1) and its ester congener SDZ 205557 (2), a 5-HT4 receptor antag onist, were prepared by O-alkylation of 4-amino-5-chloro-2-methoxybenz oate with N-(2-chloroethyl)) substituted alicyclic amines. The bromo a nd iodo analogue of compound 13b (2-(1-piperidinyl)ethyl 4-amino-5-chl oro-2-methoxybenzoate) were obtained by halogenation of dechloro-13b w ith N-halogenated succinimides. The series was evaluated in functional in vitro assays with regard to affinity for serotoninergic 5-HT4, 5-H T3 and muscarinic M(3) receptors, The affinities for 5-HT3 and M(3) re ceptors were below 6.0 (pK(B) or pA(2)). On 5-HT4 receptors in guinea- pig ileal longitudinal muscle and rat oesophagus, the majority of comp ounds 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 seri es. The enantiomers of 13g ((R)- and (S)-2-(2-methyl-1-piperidinyl)eth yl 4-amino-5-chloro-2-methoxybenzoate) interacted stereoselectively wi th 5-HT4 receptors and displayed enantiomeric potency ratios (R)/(S) o f 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 antag onist affinity and relative agonist potency within each assay (r(2) > 0.91). The new compounds may serve as academic tools in evaluating the functional role of 5-HT4 receptors. The selective partial 5-HT4 recep tor agonists presented in this paper may be useful to restore physiolo gical motility and secretion in the gut with reduced or absent propens ity to elicit tachycardia and desensitization of the intestinal target receptor.