title: N-Methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of cannabinoid receptors agonists with low CNS penetration.
abstract: Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Montreal, 7171 Frederick-Banting, Saint-Laurent, Quebec, Canada H4S 1Z9.
authors.forename: Zhongyong
authors.initials: Z
authors.lastname: Wei
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Ziping
authors.initials: Z
authors.lastname: Liu
authors.forename: Maxime
authors.initials: M
authors.lastname: Tremblay
authors.forename: Shawn
authors.initials: S
authors.lastname: Johnstone
authors.forename: Sara
authors.initials: S
authors.lastname: Béha
authors.forename: Shi Yi
authors.initials: SY
authors.lastname: Yue
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Miroslaw J
authors.initials: MJ
authors.lastname: Tomaszewski
authors.forename: William
authors.initials: W
authors.lastname: Brown
authors.forename: Christopher
authors.initials: C
authors.lastname: Walpole
authors.forename: Stéphane
authors.initials: S
authors.lastname: St-Onge
authors.forename: Etienne
authors.initials: E
authors.lastname: Lessard
authors.forename: Anne-Julie
authors.initials: AJ
authors.lastname: Archambault
authors.forename: Thierry
authors.initials: T
authors.lastname: Groblewski
authors.forename: Daniel
authors.initials: D
authors.lastname: Pagé
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002227:Carbazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000378:metabolism; D006801:Humans; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C575091:(R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide; D000700:Analgesics; D002227:Carbazoles; D043884:Receptor, Cannabinoid, CB1