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Eur J Med Chem. 2012 Dec;58:396-404. doi: 10.1016/j.ejmech.2012.10.031. Epub 2012 Oct 26.

Scaffold hopping strategy toward original pyrazolines as selective CB₂ receptor ligands.

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INSA de Rouen, Avenue de l'Université, 76800 St Etienne du Rouvray, France.


In line of a scaffold hopping strategy of pyrazole structures, especially known as potent CB(2) receptor antagonists, we exploited an original and convergent synthesis of a new class of C4-benzyl pyrazolines and derivatives from readily available hydrazones and enones (two or three steps). Making use of a mixture of resin supported reagents strategy an efficient domino process allowed the easy construction of various dihydropyrazoles in 63-83% yields. The obtained family of pyrazolines featured significant hCB(2)/hCB(1) selectivity in favor of hCB(2) receptors while more than 1000-3000 nM affinity was only measured for hCB(1) receptors. This is closely related to pyrazole SR144528 inverse agonist/antagonist, although a partial agonist behavior in the [(35)S]-GTPγS binding assay was mainly measured in our case pointing out a functional switch in action. Furthermore, this hCB(2) selectivity is unique within the pyrazoline CB ligands although the affinity ranging from 251 to 689 nM remains to be improved which give, however, an opportunity for further structure-activity relationship.

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