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Vol. 280, Issue 1, 402-409, 1997
Departments of
Pharmacology (T.J.A., S.A.W., T.P.D.) and
Chemistry
(V.J.H.), University of Arizona, College of Medicine, Tucson, Arizona
D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2
(CTAP) is a cyclic, penicillamine-containing octapeptide that is
structurally similar to somatostatin and displays greater antagonist
potency and selectivity for µ-opioid receptors, compared with the
classical µ-selective antagonist
D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2.
The aim of this study was to determine whether CTAP can enter the
central nervous system (CNS) by crossing either the blood-brain barrier or the blood-cerebrospinal fluid barrier (CSF) and to characterize the
mechanism of CNS entry. CNS entry of [3H]CTAP was
compared with that of the vascular space marker
[14C]inulin and the µ-agonist
[3H]morphine. By using an in situ brain
perfusion technique coupled to high-performance liquid chromatographic
analysis, greater amounts of radioactivity were detected in the brain
or CSF at most time points for [3H]CTAP, compared with
[14C]inulin. [3H]CTAP was found to remain
predominantly intact in the brain after a 20-min rat brain perfusion
(62.8%). CTAP was also stable in the blood and serum of rats
(T1/2 > 500 min), showing that the structure of this
peptide offers enzymatic resistance. Additionally, [3H]CTAP was found to be extensively protein-bound to
albumin in the perfusion medium (68.2%) and to proteins in rat serum
(84.2%). Entry into the brain and CSF was not inhibited by the
addition of unlabeled CTAP to the perfusion medium, suggesting that
passage into the CNS is most likely through diffusion across the
membranes that comprise the blood-brain barrier, rather than by
saturable transport. Also, greater amounts of
[3H]morphine entered both the brain and CSF after a
20-min brain perfusion, compared with [3H]CTAP. The
increased CNS penetration observed for [3H]morphine,
compared with [3H]CTAP, is likely due to the increased
lipophilicity of morphine, as shown by its higher octanol/saline
partition coefficient. Based on the pharmacokinetic profile, CTAP may
be a promising µ-selective antagonist that can be used as a treatment
for opiate overdose or addiction and also as a pharmacological tool to
further understand opioid neurobiology.
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