title: γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.
abstract: An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Saint-Laurent, Quebec, Canada. mirek.tomaszewski@astrazeneca.com
authors.forename: Yun-Xing
authors.initials: YX
authors.lastname: Cheng
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Pourashraf
authors.forename: Xuehong
authors.initials: X
authors.lastname: Luo
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Christopher
authors.initials: C
authors.lastname: Walpole
authors.forename: Dominic
authors.initials: D
authors.lastname: Salois
authors.forename: Stephane
authors.initials: S
authors.lastname: St-Onge
authors.forename: Kemal
authors.initials: K
authors.lastname: Payza
authors.forename: Etienne
authors.initials: E
authors.lastname: Lessard
authors.forename: Xiao Hong
authors.initials: XH
authors.lastname: Yu
authors.forename: Mirosław J
authors.initials: MJ
authors.lastname: Tomaszewski
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002186:Cannabinoids / Q000819:agonists*; D002243:Carbolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004355:Drug Stability; D006801:Humans; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D051381:Rats; D012995:Solubility
chemical_list: D000700:Analgesics; D002186:Cannabinoids; D002243:Carbolines