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Synthesis and biological evaluation of (3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

Abstract：

: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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Presley CS,Mustafa SM,Abidi AH,Moore BM 2nd

doi

10.1016/j.bmc.2015.07.057

subject

Has Abstract

pub_date

2015-09-01 00:00:00

pages

5390-401

issue

17

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)00641-0

journal_volume

23

pub_type

杂志文章

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