Design, synthesis, and pharmacological characterization of indol-3-ylacetamides, indol-3-yloxoacetamides, and indol-3-ylcarboxamides: potent and selective CB2 cannabinoid receptor inverse agonists.

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Pasquini S, Mugnaini C, Ligresti A, Tafi A, Brogi S, Falciani C, Pedani V, Pesco N, Guida F, Luongo L, Varani K, Borea PA, Maione S, Di Marzo V, Corelli F

Design, synthesis, and pharmacological characterization of indol-3-ylacetamides, indol-3-yloxoacetamides, and indol-3-ylcarboxamides: potent and selective CB2 cannabinoid receptor inverse agonists.

J Med Chem. 2012 Jun 14;55(11):5391-402. doi: 10.1021/jm3003334. Epub 2012 May 16.

PubMed ID

22548457 [ View in PubMed

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Abstract

In our search for new cannabinoid receptor modulators, we describe herein the design and synthesis of three sets of indole-based ligands characterized by an acetamide, oxalylamide, or carboxamide chain, respectively. Most of the compounds showed affinity for CB2 receptors in the nanomolar range, with K(i) values spanning 3 orders of magnitude (377-0.37 nM), and moderate to good selectivity over CB1 receptors. Their in vitro functional activity as inverse agonists was confirmed in vivo in the formalin test of acute peripheral and inflammatory pain in mice, in which compounds 10a and 11e proved to be able to reverse the effect of the CB2 selective agonist COR167.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rimonabant	Cannabinoid receptor 1	Ki (nM)	12	N/A	N/A	Details