title: 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists.
abstract: Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.
authors.affiliation: Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
authors.forename: R D
authors.initials: RD
authors.lastname: Clark
authors.forename: A B
authors.initials: AB
authors.lastname: Miller
authors.forename: J
authors.initials: J
authors.lastname: Berger
authors.forename: D B
authors.initials: DB
authors.lastname: Repke
authors.forename: K K
authors.initials: KK
authors.lastname: Weinhardt
authors.forename: B A
authors.initials: BA
authors.lastname: Kowalczyk
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: D W
authors.initials: DW
authors.lastname: Bonhaus
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: A D
authors.initials: AD
authors.lastname: Michel
mesh_terms: D000818:Animals; D002945:Cisplatin; D003198:Computer Simulation; D004285:Dogs; D005289:Ferrets; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D000077924:Palonosetron; D011728:Pyridones / Q000138:chemical synthesis* / Q000378:metabolism; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D007546:Isoquinolines; D011728:Pyridones; D011812:Quinuclidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D000077924:Palonosetron; D002945:Cisplatin