Synthesis and antinociceptive activity of [D-Ala2]Leu-enkephalin derivatives conjugated with the adamantane moiety.
Based on the physicochemical and pharmacological properties of drugs having an adamantane skeleton, an adamantane-based moiety was evaluated as a drug carrier for poorly absorbed compounds, including peptides, active towards the central nervous system (CNS). Seven [D-Ala2]Leu-enkephalin derivatives conjugated with an adamantane-based moiety at the C-terminus or N-terminus were prepared by the solution-phase method and their biological activities were examined. The compounds derivatized at the C-terminus through an ester or amide linkage were much more lipophilic than the parent peptide and exhibited moderate in vitro opioid activity (guinea-pig ileum assay). Among them, four derivatives (1, 2, 4, 5), exhibited significant antinociceptive effects in an in vivo assay (mouse tail-pressure test) after subcutaneous administration. This result suggests that the introduction of the lipophilic adamantane moiety into [D-Ala2]Leu-enkephalin would improve the permeation of the poorly absorbed parent peptide through the blood-brain-barrier (BBB) without loss of antinociceptive effect.
Kitagawa
K
K
Niigata College of Pharmacy, Japan.
Mizobuchi
N
N
Hama
T
T
Hibi
T
T
Konishi
R
R
Futaki
S
S
D000218:Adamantane / Q000737:chemistry*; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004558:Electric Stimulation; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010147:Pain Measurement; D012995:Solubility
D000700:Analgesics; D004743:Enkephalin, Leucine; D000218:Adamantane