Kitagawa K, Mizobuchi N, Hama T, Hibi T, Konishi R, Futaki S
Niigata College of Pharmacy, Japan.
Chem Pharm Bull (Tokyo). 1997 Nov;45(11):1782-7. doi: 10.1248/cpb.45.1782.
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.
基于具有金刚烷骨架的药物的物理化学和药理学性质，金刚烷基部分被评估为包括对中枢神经系统（CNS）有活性的肽在内的吸收不良化合物的药物载体。通过溶液相法制备了七种在C末端或N末端与金刚烷基部分缀合的[D-Ala2]亮氨酸脑啡肽衍生物，并检测了它们的生物学活性。通过酯或酰胺键在C末端衍生化的化合物比母体肽更具亲脂性，并表现出适度的体外阿片样活性（豚鼠回肠试验）。其中，四种衍生物（1、2、4、5）在皮下给药后的体内试验（小鼠尾压试验）中表现出显著的抗伤害感受作用。该结果表明，将亲脂性金刚烷基部分引入[D-Ala2]亮氨酸脑啡肽可改善吸收不良的母体肽透过血脑屏障（BBB）的渗透，而不会丧失抗伤害感受作用。
