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Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazol-based ligands for CB1 and CB2 cannabinoid receptors

Mussinu, Jean-Mario and Ruiu, Stefania and Mulè, Antonio Calogero and Pau, Amedeo and Carai, Mauro A. M. and Loriga, Giovanni and Murineddu, Gabriele and Pinna, Gérard Aimé (2003) Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazol-based ligands for CB1 and CB2 cannabinoid receptors. Bioorganic & Medicinal Chemistry, Vol. 11 (2), p. 251-263. ISSN 0968-0896. Article.

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DOI: 10.1016/S0968-0896(02)00319-X

Abstract

Cannabinoids receptors, cellular elements of the endocannabinoid system, have been the focus of extensive studies because of their potential functional role in several important physiological and pathological processes. To further evaluate the properties of CB receptors, especially CB1 and CB2 subtypes, we have designed, using SR141716A as a benchmark, a new series of rigid 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides. Compounds 1 were synthesized from substituted 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acids and requisite amines. The various analogues were assayed for binding both to the brain and peripheral cannabinoid receptors (CB1 and CB2). Seven of the new compounds displayed very high in vitro CB2 binding affinities, especially 1a, 1b, 1c, 1e, 1g, 1h and 1j which showed Ki values of 0.34, 0.225, 0.27, 0.23, 0.385, 0.037 and 0.9 nM, respectively. Compounds 1a, 1b, 1c and 1h showed the highest selectivity for CB2 receptor with Ki(CB1) to Ki(CB2) ratios of 6029, 5635, 5814 and 9810, respectively. Noticeably, 1h exhibited the highest affinity and selectivity for CB2 receptors.

Item Type:Article
ID Code:393
Status:Published
Refereed:Yes
Uncontrolled Keywords:Central nervous system, halogen organic compounds, CB1 cannabinoid receptor, CB2 cannabinoid receptor, biological fixation, piperazine derivatives, pyrrolidine derivatives, piperidine derivatives, benzene derivatives, organic hydrazide, aromatic compound, tricyclic compound, nitrogen heterocycle, chemical synthesis
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
001 Università di Sassari > 01 Dipartimenti > Scienze del farmaco
Publisher:Pergamon-Elsevier Science
ISSN:0968-0896
Copyright Holders:© 2002 Elsevier Science
Deposited On:18 Aug 2009 10:02

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