title: Design, synthesis, and pharmacological characterization of indol-3-ylacetamides, indol-3-yloxoacetamides, and indol-3-ylcarboxamides: potent and selective CB2 cannabinoid receptor inverse agonists.
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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.forename: Valentina
authors.initials: V
authors.lastname: Pedani
authors.forename: Nicolò
authors.initials: N
authors.lastname: Pesco
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy / Q000276:immunology; D010147:Pain Measurement; D011869:Radioligand Assay; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007155:Immunologic Factors; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP