RT Journal Article
SR Electronic
T1 Structure-Activity Relationships of a Series of [<span class="sc">d</span>-Ala<sup>2</sup>]Deltorphin  I and II Analogues;<em>in Vitro</em> Blood-Brain Barrier Permeability and Stability
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 817
OP 825
VO 281
IS 2
A1 Sarah A. Thomas
A1 Thomas J. Abbruscato
A1 Vincent S. Hau
A1 Terrence J. Gillespie
A1 Joseph Zsigo
A1 Victor J. Hruby
A1 Thomas P. Davis
YR 1997
UL http://jpet.aspetjournals.org/content/281/2/817.abstract
AB [d-Ala2]deltorphins are enzymatically stable, amphibian heptapeptides that have a higher affinity and selectivity fordelta-opioid receptors than any endogenous mammalian compound known. This study investigated the in vitroblood-brain barrier permeability, using primary bovine brain microvessel endothelium culture, and the resistance to enzymatic degradation, in mouse 15% brain membrane homogenates and 100% plasma, of [d-Ala2]deltorphin I, [d-Ala2]deltorphin II and several analogues. Derivatives were designed with the addition of N-terminal neutral and basic amino acids or with alterations of the amino acids present within the deltorphin sequences. The results indicated that the N-terminal sequence and the amino acids in position 4 and 5 are critical to deltorphin analogue BBB permeability and biological stability,i.e., t½ brain; 4.8 hr- [d-Ala2]deltorphin I; &gt;15 hr- [d-Ala2,Ser4,d-Ala5]deltorphin. Although, no analogue was found to increase the BBB permeability coefficient (PC; ×10−4 cm/min) of the parent compounds ([d-Ala2]deltorphin II, PC = 23.49 ± 2.42) analogues were identified: [Arg0,d-Ala2]deltorphin II, PC = 19.06 ± 3.73 and [Pro−1,Pro0,d-Ala2]deltorphin II, PC = 22.22 ± 5.93; which had similar permeability coefficients, even though they had larger molecular weights and, in the case of the cationic pro-drug, a significantly lower lipophilicity. These analogues provide directions in the development of future pro-drugs for the treatment of pain and this study further clarifies the structure-activity relationship of the deltorphins. The American Society for Pharmacology and Experimental Therapeutics