Premium
Preparation and In Vitro Pharmacology of 5‐HT 4 Receptor Ligands. Partial Agonism and Antagonism of Metoclopramide Analogous Benzoic Esters
Author(s) -
Elz Sigurd,
Keller Andreas
Publication year - 1995
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19953280705
Subject(s) - chemistry , benzamide , stereochemistry , agonist , alicyclic compound , partial agonist , receptor , muscarinic acetylcholine receptor , antagonist , biochemistry , polymer chemistry
Alicyclic ester analogues of the gastroprokinetic benzamide metoclopramide ( 1 ) and its ester congener SDZ 205557 ( 2 ), a 5‐HT 4 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‐HT 4 , 5‐HT 3 and muscarinic M 3 receptors. The affinities for 5‐HT 4 and M 3 receptors were below 6.0 (p K B or pA 2 ). On 5‐HT 4 receptors in guinea‐pig ileal longitudinal muscle and rat oesophagus, the majority of compounds revealed partial 5‐HT 4 receptor agonism susceptible to blockade by SDZ 205557, a reference 5‐HT 4 receptor antagonist (p K 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‐HT 4 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 ( r 2 > 0.91). The new compounds may serve as academic tools in evaluating the functional role of 5‐HT 4 receptors. The selective partial 5‐HT 4 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.