The new multitarget antinociceptive agent, 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1), combines MOR agonist–DOR antagonist activity. This benzomorphan-based compound showed to be as potent as morphine in acute pain (Pasquinucci et al., 2010) but without the morphine-like side effects (McDonald and Lambert, 2008). In fact, the most of clinically used opioid analgesics are MOR agonist, and as a consequence, tolerance to analgesic effect occurs in their long term use. Thanks to its low capability to induce tolerance, LP1 should be an interesting candidate as analgesic for persistent pain conditions requiring long term therapies. Unfortunately LP1 shows low water solubility, and for this reason, to date, all tests have been performed using LP1 oxalate. Because oxalate causes several harmful effects, especially in the kidney, our goal is to achieve a suitable formulation for the administration of LP1 as free base. The incapsulation of LP1, both as oxalate salt and free base, in liposomes (multilamellar vescicles (MLV) of dimyristoylphosphatidylcholine) was considered and their interaction was evaluated using Differential Scanning Calorimetry. This study allow us to compare the interaction and absorption by the phospholipid bilayers (Sarpietro et al., 2012) of LP1 and LP1 oxalate. The results suggest that LP1 has a better interaction with the biomembrane with respect to LP1 oxalate. But when solid LP1 was put in contact with the MLV aqueous dispersion, it was not able to cross the medium and reach the phospholipid surface to be absorbed. Instead LP1 oxalate showed better results. Moreover, the LP1 and LP1 oxalate release by a liposomal carrier to a biomembrane model was also evaluated. In these experiments both compounds showed a good transfer profile. In the light of these results, studies to obtain a LP1 delivery system are in progress. In fact, as LP1 is released by the liposomal carrier, a delivery system would allow a greater bioavailability without the potential side effects related to the use of oxalate.
INTERACTION OF A NEW ANALGESIC AGENT, LP1, WITH THE BIOMEMBRANE MODELS: CALORIMETRIC STUDY
CASTELLI, Francesco;PASQUINUCCI, Lorella Giuseppina
2013-01-01
Abstract
The new multitarget antinociceptive agent, 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1), combines MOR agonist–DOR antagonist activity. This benzomorphan-based compound showed to be as potent as morphine in acute pain (Pasquinucci et al., 2010) but without the morphine-like side effects (McDonald and Lambert, 2008). In fact, the most of clinically used opioid analgesics are MOR agonist, and as a consequence, tolerance to analgesic effect occurs in their long term use. Thanks to its low capability to induce tolerance, LP1 should be an interesting candidate as analgesic for persistent pain conditions requiring long term therapies. Unfortunately LP1 shows low water solubility, and for this reason, to date, all tests have been performed using LP1 oxalate. Because oxalate causes several harmful effects, especially in the kidney, our goal is to achieve a suitable formulation for the administration of LP1 as free base. The incapsulation of LP1, both as oxalate salt and free base, in liposomes (multilamellar vescicles (MLV) of dimyristoylphosphatidylcholine) was considered and their interaction was evaluated using Differential Scanning Calorimetry. This study allow us to compare the interaction and absorption by the phospholipid bilayers (Sarpietro et al., 2012) of LP1 and LP1 oxalate. The results suggest that LP1 has a better interaction with the biomembrane with respect to LP1 oxalate. But when solid LP1 was put in contact with the MLV aqueous dispersion, it was not able to cross the medium and reach the phospholipid surface to be absorbed. Instead LP1 oxalate showed better results. Moreover, the LP1 and LP1 oxalate release by a liposomal carrier to a biomembrane model was also evaluated. In these experiments both compounds showed a good transfer profile. In the light of these results, studies to obtain a LP1 delivery system are in progress. In fact, as LP1 is released by the liposomal carrier, a delivery system would allow a greater bioavailability without the potential side effects related to the use of oxalate.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
