Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3-4
|
| pubmed:dateCreated |
1994-12-30
|
| pubmed:abstractText |
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)
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:issn |
0028-3908
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
33
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
515-26
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:7984291-Animals,
pubmed-meshheading:7984291-Binding, Competitive,
pubmed-meshheading:7984291-Brain Neoplasms,
pubmed-meshheading:7984291-Cell Membrane,
pubmed-meshheading:7984291-Ferrets,
pubmed-meshheading:7984291-Guinea Pigs,
pubmed-meshheading:7984291-Heart Rate,
pubmed-meshheading:7984291-Male,
pubmed-meshheading:7984291-Mucous Membrane,
pubmed-meshheading:7984291-Muscle, Smooth,
pubmed-meshheading:7984291-Naphthalimides,
pubmed-meshheading:7984291-Nausea,
pubmed-meshheading:7984291-Neostriatum,
pubmed-meshheading:7984291-Neuroblastoma,
pubmed-meshheading:7984291-Quinuclidines,
pubmed-meshheading:7984291-Rats,
pubmed-meshheading:7984291-Rats, Sprague-Dawley,
pubmed-meshheading:7984291-Receptors, Serotonin,
pubmed-meshheading:7984291-Reflex,
pubmed-meshheading:7984291-Stereoisomerism,
pubmed-meshheading:7984291-Swine,
pubmed-meshheading:7984291-Swine, Miniature,
pubmed-meshheading:7984291-Tumor Cells, Cultured,
pubmed-meshheading:7984291-Vomiting
|
| pubmed:articleTitle |
(R) and (S) RS 56532: mixed 5-HT3 and 5-HT4 receptor ligands with opposing enantiomeric selectivity.
|
| pubmed:affiliation |
Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA 94304.
|
| pubmed:publicationType |
Journal Article,
In Vitro
|