-
Zhongyong Wei,
Hua Yang,
Ziping Liu,
Maxime Tremblay,
Shawn Johnstone,
Sara Béha,
Shi Yi Yue, Sanjay Srivastava,
Miroslaw J Tomaszewski,
William Brown,
Christopher Walpole,
Stéphane St-Onge,
Etienne Lessard,
Anne-Julie Archambault,
Thierry Groblewski,
Daniel Pagé
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 05/2012; 22(12):3884-9. · 2.65 Impact Factor
-
Yun-Xing Cheng,
Mehrnaz Pourashraf,
Xuehong Luo, Sanjay Srivastava,
Christopher Walpole,
Dominic Salois,
Stephane St-Onge,
Kemal Payza,
Etienne Lessard,
Xiao Hong Yu,
Mirosław J Tomaszewski
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 02/2012; 22(4):1619-24. · 2.65 Impact Factor
-
Daniel Pagé,
Elise Balaux,
Luc Boisvert,
Ziping Liu,
Claire Milburn,
Maxime Tremblay,
Zhongyong Wei,
Simon Woo,
Xuehong Luo,
Yun-Xing Cheng, [......],
Fei Zhou,
William Brown,
Miroslaw Tomaszewski,
Christopher Walpole,
Leila Hodzic,
Stéphane St-Onge,
Claude Godbout,
Dominic Salois,
Kemal Payza,
Keymal Payza
[show abstract]
[hide abstract]
ABSTRACT: The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.
Bioorganic & medicinal chemistry letters 07/2008; 18(13):3695-700. · 2.65 Impact Factor
