We investigated the pharmacokinetic properties of D 9 -tetrahydrocannabinol (D 9 -THC), the main psychoactive constituent of cannabis, in adolescent and adult male mice. The drug was administered at logarithmically ascending doses (0.5, 1.6, and 5 mg/kg, i.p.) to pubertal adolescent (37-day-old) and adult (70day-old) mice. D 9 -THC and its first-pass metabolites-11hydroxy-D 9 -THC and 11-nor-9-carboxy-D 9 -THC (11-COOH-THC)-were quantified in plasma, brain, and white adipose tissue (WAT) using a validated isotope-dilution liquid chromatography/tandem mass spectrometry assay. D 9 -THC (5 mg/kg) reached 50% higher circulating concentration in adolescent mice than in adult mice. A similar age-dependent difference was observed in WAT. Conversely, 40%-60% lower brain concentrations and brain-to-plasma ratios for D 9 -THC and 50%-70% higher brain concentrations for D 9 -THC metabolites were measured in adolescent animals relative to adult animals. Liver microsomes from adolescent mice converted D 9 -THC into 11-COOH-THC twice as fast as adult microsomes. Moreover, the brains of adolescent mice contained higher mRNA levels of the multidrug transporter breast cancer resistance protein, which may extrude D 9 -THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity. Finally, administration of D 9 -THC (5 mg/kg) reduced spontaneous locomotor activity in adult, but not adolescent, animals. The results reveal the existence of multiple differences in the distribution and metabolism of D 9 -THC between adolescent and adult male mice, which might influence the pharmacological response to the drug. SIGNIFICANCE STATEMENTAnimal studies suggest that adolescent exposure to D 9 -tetrahydrocannabinol (D 9 -THC), the intoxicating constituent of cannabis, causes persistent changes in brain function. These studies generally overlook the impact that age-dependent changes in the distribution and metabolism of the drug might exert on its pharmacological effects. This report provides a comparative analysis of the pharmacokinetic properties of D 9 -THC in adolescent and adult male mice and outlines multiple functionally significant dissimilarities in the distribution and metabolism of D 9 -THC between these two age groups.

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT/MT agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.