Prokai-Tatrai K, Prokai L, Bodor N
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville 32610-0497, USA.
J Med Chem. 1996 Nov 22;39(24):4775-82. doi: 10.1021/jm960356e.
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.
基于逆向代谢药物设计的脑靶向化学递送系统（CDS）被应用于亮氨酸脑啡肽类似物，即酪氨酰-D-丙氨酰-甘氨酰-苯丙氨酰-D-亮氨酸（DADLE）。肽CDS的分子结构使其肽性质能够躲避神经肽降解酶的作用，并为穿透血脑屏障提供亲脂性、生物可逆性功能。这些功能由N端的靶向基团1,4-二氢胡芦巴基和C端的一个庞大亲脂性酯基提供。在靶向基团和母体肽之间还插入了一个间隔氨基酸残基，以确保DADLE能被特定酶释放。通过片段偶联法合成了四种CDS，在获得这类肽缀合物方面，该方法被证明优于顺序延伸法。通过甩尾潜伏期测量监测，静脉注射这些化合物在大鼠体内产生了显著且持久的反应。具有较大胆甾醇基团的CDS比具有较小1-金刚烷乙酯基团的CDS显示出更好的疗效。间隔基团是控制DADLE释放速率从而控制药理活性的最重要因素；脯氨酸作为间隔基团比丙氨酸产生更强效的镇痛作用。CDS的镇痛作用可被纳洛酮逆转，但不能被甲基纳洛酮铵逆转，这证实了中枢阿片受体是介导由肽CDS诱导的镇痛作用的唯一原因，该肽CDS在脑内递送、保留并随后释放该肽。
