The interaction of RS 25259‐197, a potent and selective antagonist, with 5‐HT₃ receptors, in vitro

Abstract

1 A series of isoquinolines have been identified as 5-HT3 receptor antagonists. One of these, RS 25259-197 [(3aS)-2-[(S)-l-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-l-oxo-lH-benzo [de]isoquinoline-hydrochloride], has two chiral centres. The remaining three enantiomers are denoted as RS 25259-198 (R,R), RS25233-197 (S,R) and RS25233-198 (R,S). 2 At 5-HT3 receptors mediating contraction of guinea-pig isolated ileum, RS 25259-197 antagonized contractile responses to 5-HT in an unsurmountable fashion and the apparent affinity (pKB), estimated at 10 nM, was 8.8 ± 0.2. In this tissue, the -log KB values for the other three enantiomers were 6.7 ± 0.3 (R,R), 6.7 ± 0.1 (S,R) and 7.4 ± 0.1 (R,S), respectively. The apparent affinities of RS 25259-197 and RS 25259-198, RS 25233-197 and RS 25233-198 6 Quantitative autoradiographic studies in rat brain indicated a differential distribution of 5-HT3 receptor sites by [3H]-RS . High densities of sites were seen in nuclear tractus solitaris and area postrema, a medium density in spinal trigeminal tract, ventral dentate gyrus and basal medial amygdala, and a low density of sites in hippocampal CAl, parietal cortex, medium raphe and cerebellum. 7 In conclusion, the functional, binding and distribution studies undertaken with the radiolabelled and non-radiolabelled RS 25259-197 (S,S enantiomer) established the profile of a highly potent and selective 5-HT3 receptor antagonist.

Pharmacological characterization of RS 25259‐197, a novel and selective 5‐HT3 receptor antagonist, in vivo

“…*Statistically significant from vehicle control (P<0.05). (Wong et al, 1994) whereas the reported pKi values for ondansetron and granisetron in rat tissues range from 8.3-9.0 (for ondansetron) and from 9.2-9.8 (for granisetron) (Kilpatrick et al, 1990 Oral administration of drugs to cancer patients undergoing chemotherapy is problematic owing to the high incidence of emesis in these patients. Thus, availability of a 5-HT3 receptor antagonist in the form of a transdermal formulation would greatly facilitate the management of emesis in these patients.…”

Efficacy of palonosetron for preventing postoperative nausea and vomiting: a systematic review and meta-analysis

“…[13][14][15][16][17] Palonosetron may also have other advantages for perioperative care. For example, a recent study reported by Cho et al 34 found that palonosetron 0.075 mg iv administered before induction of anesthesia reduced injection pain associated with rocuronium administration; the NNT was 2.94.…”

“…Méthodes Nous avons effectué une recherche systématique dans les bases de données MEDLINE Ò , EMBASE TM , le Registre central Cochrane des essais cliniques contrô lés et Web of Science Ò pour identifier les essais randomisés contrô lés qui ont abordé la comparaison de l'efficacité antiémétique dans les 24 premières heures suivant une chirurgie, du palonosétron et de l'ondansétron administrés à titre prophylactique. Les principaux critères d'évaluation étaient le pourcentage de participants éprouvant des nausées postopératoires (NPO), des vomissements postopératoires (VPO) ou les deux, dans la période précoce (0-6 heures) ou tardive (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) Postoperative nausea and vomiting (PONV), the big ''little problem'', 1 is the most common postoperative medical problem. From the perspective of both patients and healthcare providers, prophylaxis of PONV is equally as important as postoperative analgesia.…”

“…13,14 In addition, Rojas et al [15][16][17] showed features that differentiate palonosetron from other 5-HT 3 RAs: allosteric binding and positive cooperativity with 5-HT 3 R, triggering of 5-HT 3 R internalization and prolonged inhibition of receptor function, and inhibition of substance P (a mediator of emesis)-mediated responses. [15][16][17] Due to these unique characteristics, palonosetron may be a promising agent that could achieve long-lasting efficacy in the prevention of PONV.…”

Palonosetron and dexamethasone for prevention of nausea and vomiting in patients receiving high-dose chemotherapy with auto-SCT

“…30 Starting from our experience with palonosetron plus dexamethasone in multiple-day CT, 29 the present study evaluated the efficacy, in terms of complete response (no emesis, no rescue therapy), of a single dose of palonosetron administered on the first day of a conditioning regimen together with dexamethasone administered throughout the entire period of conditioning in hematological patients receiving HD-CT and auto-SCT.…”