(R)-RS-56532 AND (S)-RS-56532 - MIXED 5-HT3 AND 5-HT4 RECEPTOR LIGANDS WITH WITH OPPOSING ENANTIOMERIC SELECTIVITY

The pharmacological properties of the (R) and (S) enantiomers of RS 56 532 have been studied in vitro and in vivo. In radioligand binding stu dies at 5-HT4, receptors in guinea-pig striatum, (S) RS 56532 exhibite d a higher affinity than (R) RS 56532 (-log K-i = 7.6 and 6.5, respect ively). (S) RS 56532 acted as a potent agonist at 5-HT4 receptors medi ating relaxation of rat oesophageal muscularis mucosae (-log EC(50) = 7.9) while (R) RS 56532 acted as a weaker agonist at this receptor (-l og EC(50) < 6.0). These data suggest that at 5-HT4 receptors, the enan tiomeric selectivity of RS 56532 was (S) >(R). In binding studies at 5 -HT3 receptors in rat cortex, (R) RS 56532, conversely, exhibited a hi gher affinity than (R) RS 56532 (-log K-i = 9.1 and 8.0, respectively) . At 5-HT3 receptors in guinea-pig isolated ileum, (R) RS 56532 exhibi ted an affinity (-log K-B of 7.9, whereas (S) RS 56532 (1 nM-1 mu M) w as inactive. No agonism was observed at ileal 5-HT3 receptors with eit her 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 56 532 exhibited a higher affinity than (S) RS 56532 (-log K-i = 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 hi gh affinity (-log K-i = 7.5) by the (R), but not (S) enantiomer, of RS 42358 (-log K-i = 4.7). Since (S) RS 42358 is a high affinity 5-HT3 r eceptor antagonist, these data further highlight the dissimilarity bet ween the 5-HT, receptor and the '(R) zacopride' site. The '(R) zacopri de' site also appeared to be pharmacologically distinct from the 5-HT4 receptor, since 5-HT4 ligands such as renzapride, SDZ 205,557 or RS 2 3597-190 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-de pendent tachycardia (ED(50) = 3 mu g kg(-1) i.v.; maximum response = 9 0-100 beats min(-1)). (S) RS 56532 increased heart rate by 88 min(-1) with a potency of (ED(50)) of 3 mu g kg(-1), i.v. In contrast, a tachy cardia effect (23 beats min(-1)) of (R) RS 56532 was seen only at 1 mg kg(-1), i.v.(R) RS 56532 was more potent than (S) RS 56532 (ID50 = 3 and 78 mu g kg(-1), i.v. respectively) at inhibiting the von Bezold Ja risch reflex, a response mediated by 5-HT, receptor activation. Simila rly, (R) RS 56532, at 0.1 mg kg(-1) p.o., inhibited cisplatin induced emesis in the ferret, from 19.8 to 5.8 emetic episodes. In contrast, ( S) RS 56532 was inactive at this oral dose. The emetic response to neo plastic agents such as cisplatin is also mediated by 5-HT3 activation. In summary, RS 56532 in vitro and in vivo, exhibits opposing enantiom eric selectivity at 5-HT3 and 5-HT4 receptors, i.e. 5-HT3-(R) > (S); 5 -HT4-(S) > (R). The affinity of the (R) enantiomer at 5-HT3 receptors and the potency of the (S) enantiomer at 5-HT4 receptors render them u seful pharmacological tools to further define the binding domains of t hese two 5-HT receptor subtypes. Furthermore, these data show that 1,8 -naphthalimides, such as (S) RS 56532, represent a novel class of pote nt 5-HT4 receptor agonists.