Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

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.