Design, synthesis, and structure–activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists

• Published in: Bioorganic & medicinal chemistry letters 2010-12, Vol.20 (24), p.7327-7330
• Main Authors: Moir, Elizabeth M., Yoshiizumi, Kazuya, Cairns, Jim, Cowley, Phillip, Ferguson, Morag, Jeremiah, Fiona, Kiyoi, Takao, Morphy, Richard, Tierney, Jason, Wishart, Grant, York, Mark, Baker, James, Cottney, Jean E., Houghton, Andrea K., McPhail, Petula, Osprey, Andrew, Walker, Glenn, Adam, Julia M.
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Analgesics; Animals; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds - chemistry; Cannabinoid CB1 receptor; Drug Design; GPCR agonist; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Mice; Microsomes, Liver - metabolism; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.10.061

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.