(R) and (S) RS 56532: mixed 5-HT3 and 5-HT4 receptor ligands with opposing enantiomeric selectivity

The pharmacological properties of the (R) and (S) enantiomers of RS 56532 have been studied in vitro and in vivo. In radioligand binding studies at 5-HT4 receptors in guinea-pig striatum, (S) RS 56532 exhibited a higher affinity than (R) RS 56532 (-log Ki = 7.6 and 6.5, respectively). (S) RS 56532 acted as a potent agonist at 5-HT4 receptors mediating relaxation of rat oesophageal muscularis mucosae (-log EC50 = 7.9) while (R) RS 56532 acted as a weaker agonist at this receptor (-log EC50 < 6.0). These data suggest that at 5-HT4 receptors, the enantiomeric selectivity of RS 56532 was (S) > (R). In binding studies at 5-HT3 receptors in rat cortex, (R) RS 56532, conversely, exhibited a higher affinity than (R) RS 56532 (-log Ki = 9.1 and 8.0, respectively). At 5-HT3 receptors in guinea-pig isolated ileum, (R) RS 56532 exhibited an affinity (-log KB) of 7.9, whereas (S) RS 56532 (1 nM-1 microM) was inactive. No agonism was observed at ileal 5-HT3 receptors with either enantiomers. These data suggest that at 5-HT3 receptors in rat and guinea-pig, both enantiomers acted as antagonists, with (R) > (S) RS 56532. At the non-5-HT3, high affinity '(R) zacopride' site, (R) RS 56532 exhibited a higher affinity than (S) RS 56532 (-log Ki = 6.1 and 4.9). This site was insensitive to potent 5-HT3 antagonists such as (R) YM 060 or ondansetron. However, it was recognized with relatively high affinity (-log Ki = 7.5) by the (R), but not (S) enantiomer, of RS 42358 (-log Ki = 4.7). Since (S) RS 42358 is a high affinity 5-HT3 receptor antagonist, these data further highlight the dissimilarity between the 5-HT3 receptor and the '(R) zacopride' site. The '(R) zacopride' site also appeared to be pharmacologically distinct from the 5-HT4 receptor, since 5-HT4 ligands such as renzapride, SDZ 205,557 or RS 23597-190 exhibited low affinities. The enantiomeric selectivity of (R) and (S) RS 56532 in vivo was consistent with findings in vitro. At 5-HT4 receptors mediating tachycardia in the pig, 5-HT induced a dose-dependent tachycardia (ED50 = 3 micrograms kg-1, i.v.; maximum response = 90-100 beats min-1). (S) RS 56532 increased heart rate by 88 min-1 with a potency of (ED50) of 3 micrograms kg-1, i.v.(ABSTRACT TRUNCATED AT 400 WORDS)