Analytical characterization of the BBB functionality of the opioid-peptides EM-1, EM-2 and CTAP.

Peptides constitute a new group of promising drugs, with a diverse range of pharmacological activities [1]. One of their most promising targets is the Central Nervous System (CNS), where the Blood-Brain Barrier (BBB) constitutes an important flux-regulating compartment [2]. The development of selective and potent opioid peptide drugs for the major opioid receptor types (µ, δ and κ OR) continues to be a key objective in pharmacological research [3]. We present here the BBB influx and efflux data of the 3 µ-opioid peptides EM-1 (endomorphin-1), EM-2 (endomorphin-2) and CTAP (connective tissue activating peptide). Limited literature data indicate that both endomorphins are transported out of the brain by a saturable transport system[4], while CTAP can enter the brain from plasma [5]. However, no comprehensive data are available. The different steps are presented: - peptide handling and quality control by LC-DAD/MS, - chemical-metabolic stability, including the in-vitro metabolic study in standard mice tissues (i.e. plasma, brain, liver and kidney); - modification to its radiotracer and related QC; - BBB experiments: in-vivo BBB influx and efflux studies on mice. These studies are part of a global QSPR-project where the chromatographic properties of peptides are linked towards their BBB behavior. References: 1. Pan, W.H., et al., Effects of peptides: a cross-listing of peptides and their central actions published in the journal Peptides from 1994 through 1998. Peptides, 1999. 20(9): p. 1127-1138. 2. Kastin A.J., P.W., Peptide transport across the blood-brain barrier, in Peptide Transport and Delivery into the Central Nervous System, L.P.a.K. Prokai-Tatrai, Editor. 2003, Birkhäuser Verlag: Basel. p. 79-100. 3. Snyder, S.H. and G.W. Pasternak, Historical review: Opioid receptors. Trends in Pharmacological Sciences, 2003. 24(4): p. 198-205. 4. Kastin, A.J., et al., Saturable brain-to-blood transport of endomorphins. Experimental Brain Research, 2001. 139(1): p. 70-75. 5. Abbruscato, T.J., et al., Blood-brain barrier permeability and bioavailability of a highly potent and mu-selective opioid receptor antagonist, CTAP: Comparison with morphine. Journal of Pharmacology and Experimental Therapeutics, 1997. 280(1): p. 402-409