The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB 1 receptors, is still a matter of debate. In the present study, we report that CB 1 and adenosine A 2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB 1 receptor signaling was found to be completely dependent on A 2A receptor activation. Accordingly, blockade of A 2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB 1 receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A 2A and CB 1 receptors.

A series of substituted 2,4,5-triphenylisothiazol-3(2H)-one 1,1-dioxides 9 was synthesized and investigated as inhibitors of human leukocyte elastase (HLE). All compounds were found to inhibit HLE in a time-dependent manner and most of them exhibited kobs/[I] values > 300M(-1)s(-1). The most potent 3-oxosultam of this series was 91 (kobs/[I] = 2440 M(-1)s(-1)). Kinetic investigations performed with 9g and different substrate concentrations did not allow to clearly distinguish between a competitive or noncompetitive mode of inhibition. A more complex interaction is supported by the failure of a linear dependency of kobs values on the inhibitor concentration.