title: Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design.
abstract: A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Try-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.
authors.affiliation: Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville 32610-0497, USA.
authors.forename: K
authors.initials: K
authors.lastname: Prokai-Tatrai
authors.forename: L
authors.initials: L
authors.lastname: Prokai
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives*; D004950:Esterases / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009538:Nicotine / Q000031:analogs & derivatives; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D000700:Analgesics; D010455:Peptides; D011355:Prodrugs; D011957:Receptors, Opioid; D009270:Naloxone; D004743:Enkephalin, Leucine; D009538:Nicotine; D004950:Esterases; D008049:Lipase; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases