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1.
Bioorg Med Chem ; 26(1): 295-307, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29229226

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.


Subject(s)
Pyridazines/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfamerazine/pharmacology , Sulfonamides/pharmacology , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Pyridazines/chemistry , Structure-Activity Relationship , Sulfamerazine/chemical synthesis , Sulfamerazine/chemistry , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
2.
J Med Chem ; 59(14): 6753-6771, 2016 07 28.
Article in English | MEDLINE | ID: mdl-27309150

ABSTRACT

A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.


Subject(s)
Multiple Sclerosis/drug therapy , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship
3.
Eur J Med Chem ; 101: 651-67, 2015 Aug 28.
Article in English | MEDLINE | ID: mdl-26209834

ABSTRACT

During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (Ki in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [(35)S]-GTPγS binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model.


Subject(s)
Camphanes/chemical synthesis , Camphanes/pharmacology , Molecular Docking Simulation , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Camphanes/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Pyrazoles/chemistry , Structure-Activity Relationship
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