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NEUROPHARMACOLOGY

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Department of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, People's Republic of China; (H.-M.L., X.-F.L., J.-L.Y., C.-L.W., Y.Y., R.W.); and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, People's Republic of China (R.W.)

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.

Address correspondence to: Dr. Rui Wang, Department of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, People's Republic of China. E-mail: wangrui{at}lzu.edu.cn