%0 Journal Article %A Hong-Mei Liu %A Xue-Feng Liu %A Jin-Long Yao %A Chang-Lin Wang %A Ye Yu %A Rui Wang %T Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1 %D 2006 %R 10.1124/jpet.106.106484 %J Journal of Pharmacology and Experimental Therapeutics %P 308-316 %V 319 %N 1 %X The endogenous μ-opioid receptor agonist, endomorphin (EM)-1, cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit analgesia when given systemically because it is severely restricted by the blood-brain barrier (BBB). To improve the physicochemical characteristics of EM-1 and subsequently achieve greater BBB permeation, we synthesized a series of EM-1 analogs by combining successful chemical modifications, including N-terminal cationization, C-terminal chloro-halogenation, and unnatural amino acid (d-Ala, Sar, and d-Pro-Gly) substitutions in position 2. Presently, their binding and bioassay activity, lipophilicity, stability, and antinociceptive activity were determined and compared. Guanidino-addition and chloro-halogenation attenuated the μ-receptor affinity to some extent, but they demonstrated differences in the influence on stability. It appeared that guanidino-addition contributed to brain stability enhancement for the greater part, whereas chloro-halogenation together with amino acid substitutions in position 2 was of more importance for the stability enhancement in serum than in brain. Determination of the octanol/buffer coefficient revealed that chloro-halogenation did compromise the decreased lipophilicity caused by guanidino-addition, and introduction of d-Ala as well as d-Pro-Gly, but not Sar, in place of l-Pro2, also increased the overall lipophilicity to some extent. Among the peptides tested, intracerebroventricular injection of guanidino-[d-Ala2, p-Cl-Phe4]EM-1 showed the strongest analgesia, being 3 times more potent than the parent peptide. We also found that in comparison with EM-1, the four d-Ala-containing tetrapeptides and the chloro-halogenated d-Pro-Gly-containing pentapeptide elicited significant and prolonged central-mediated analgesia upon subcutaneous administration, indicating that more peptides reached the CNS, eliciting greater analgesic effect. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/319/1/308.full.pdf