Biopharmaceutical aspects of the development of peptides as CNS drug delivery vectors and therapeutic agents: Studies with substance P and dynorphin A analogs

Neuropeptides show promise for development as drug delivery vectors and therapeutic agents for CNS disorders. However, their clinical application is severely limited due to the lack of understanding of the biopharmaceutical factors regulating their activity. Various studies were conducted in an attempt to recognize the factors controlling the development of substance P and dynorphin A analogs as vectors for the delivery of drug candidates and therapeutic agents for the treatment of CNS disorders respectively.; Results from these studies showed that permeation of substance P across the blood-brain barrier involves a high-affinity, low capacity transport process mediated by the neurokinin-1 receptor. Changes in the structure of dynorphin A-(1-11)NH2 were observed to have no consistent influence on its blood-brain barrier permeability. However, structural changes were found to significantly affect the metabolism and protein binding characteristics of this compound.; Pharmacokinetic studies with the lead dynorphin A analogs have revealed that these molecules exhibit rapid elimination behavior in vivo. The major factor responsible for the limited plasma exposure of these compounds was determined to be their susceptibility to endopeptidase-mediated metabolism in blood and liver.; In conclusion, substance P appears to be a promising vector for the delivery of drug compounds to the brain, while development of dynorphin A analogs as therapeutic agents will require structural modifications decrease their susceptibility to endopeptidase mediated degradation.