Biodisponibilità e farmacocinetiche nello studio del profilo farmacologico di molecole ad azione cannabinoidergica

The curative properties of Cannabis sativa L. have been known for ages, but only in the last years interesting pharmaceutical properties have been reported for both synthetic and natural compounds having high affinity towards CB1 and/or CB2 cannabinoid receptors. In particular Rimonabant and other pyrazole derivatives have been widely studied for their CB1 antagonism in different in vitro and in vivo models. The lead compound Rimonabant (SR14176A or Acomplia®) has been initially employed in human as anti-obesity drug, but unfortunately EMA was constrained to block its sales according to the evidence of related adverse effects, particularly increased incidence of depression and suicidality. However interest in cannabinoid drug discovery is actually marked, especially toward the obtainment of new CB1 and/or CB2 ligands. In order to evaluate structure-activity relationship due to the modification of the different substituents at both C4 and C5 positions of the pyrazole core, new series of cannabinoid pyrazole derivatives have been obtained. Molecular structures have been investigated by Infrared Spettroscopy, Nuclear Magnetic Resonance and Mass Spectrometry. Two of CB1 antagonist compounds, NESS014A and NESS006A, were obtained and characterized by CB1 affinity of 14.3 and 35.0 nM, respectively (expressed as Ki). To evaluate the effect of the chemical structure of the compounds on the blood and brain barrier permeability, bioanalytical methods based on high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) in both rat brain and blood were developed and validated. To investigate their adsorbition, distribution, metabolism and elimination (ADME), pharmacokinetic analysis were carried out by Compartimental Analysis at different time: pre-dose and from 2 to 1440 minutes post-dose after NESS014A and NESS006A acute infusion.