Synthesis and biological evaluation of (3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.
Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function. Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity. In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy. The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Ave., Room 327D, Memphis, TN 38163, USA.
Chaela S
CS
Presley
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Ave., Room 327D, Memphis, TN 38163, USA.
Suni M
SM
Mustafa
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Ave., Room 327D, Memphis, TN 38163, USA.
Ammaar H
AH
Abidi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Ave., Room 327D, Memphis, TN 38163, USA. Electronic address: bmoore@uthsc.edu.
Bob M
BM
Moore
D000478:Alkylation; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D054879:Halogenation; D006801:Humans; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism
D001713:Biphenyl Compounds; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
ACTOne assay; CB2 receptor; Cannabinoid; Inverse agonist; cAMP stimulation