title: Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides.
abstract: Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.
authors.affiliation: Rhône-Poulenc Rorer Central Research, King of Prussia, Pennsylvania 19406.
authors.forename: R D
authors.initials: RD
authors.lastname: Youssefyeh
authors.forename: H F
authors.initials: HF
authors.lastname: Campbell
authors.forename: J E
authors.initials: JE
authors.lastname: Airey
authors.forename: S
authors.initials: S
authors.lastname: Klein
authors.forename: M
authors.initials: M
authors.lastname: Schnapper
authors.forename: M
authors.initials: M
authors.lastname: Powers
authors.forename: R
authors.initials: R
authors.lastname: Woodward
authors.forename: W
authors.initials: W
authors.lastname: Rodriguez
authors.forename: S
authors.initials: S
authors.lastname: Golec
authors.forename: W
authors.initials: W
authors.lastname: Studt
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000932:Antiemetics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D004285:Dogs; D005289:Ferrets; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control; D014961:X-Ray Diffraction
chemical_list: D000577:Amides; D000932:Antiemetics; D001549:Benzamides; D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C073523:N-(1-azabicyclo(2.2.2)octan-3-yl)-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxamide; C073524:N-(1-azabicyclo(2.2.2)octan-3-yl)-8-chloro-2,6-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin-10-carboxamide; D012701:Serotonin; D002945:Cisplatin