Conjugation of a brain-penetrant peptide with neurotensin providesantinociceptive properties

摘要

Neurotensin (NT) has emerged as an important modulator of nociceptive transmissionand exerts its biological effects through interactions with 2 distinct GPCRs, NTS1and NTS2. NT provides strong analgesia when administered directly into the brain;however, the blood-brain barrier (BBB) is a major obstacle for effective delivery ofpotential analgesics to the brain. To overcome this challenge, we synthesizedchemical conjugates that are transported across the BBB via receptor-mediatedtranscytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDLreceptor–related protein-1 (LRP1). Using in situ brain perfusion in mice, wefound that the compound ANG2002, a conjugate of An2 and NT, was transported at least10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v.ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain.At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by thedevelopment of neuropathic and bone cancer pain in animal models. The analgesicproperties of ANG2002 demonstrated in this study suggest that this compound iseffective for clinical management of persistent and chronic pain and establish thebenefits of this technology for the development of neurotherapeutics.