Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1 receptor ligand antagonists |
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| Authors: | Gabriele Murineddu Francesco Deligia Giulio Ragusa Laura García-Toscano María Gómez-Cañas Battistina Asproni Valentina Satta Elena Cichero Ruth Pazos Paola Fossa Giovanni Loriga Javier Fernández-Ruiz Gerard A. Pinna |
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| Affiliation: | 1. Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100 Sassari, Italy;2. Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy;3. Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain;4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;5. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain;6. Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132 Genoa, Italy;g. Institute of Translational Pharmacology, National Research Council, 09010 Pula, Cagliari, Italy |
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| Abstract: | A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6?nM for CB1 receptors and >40?μM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2?nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist. |
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| Keywords: | Sulfenamides Sulfonamides Diarylpyridazines ADMET model Docking studies |
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