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OtherNEUROPHARMACOLOGY

Structure-Activity Relationships of a Series of [d-Ala2]Deltorphin I and II Analogues;in Vitro Blood-Brain Barrier Permeability and Stability

Sarah A. Thomas, Thomas J. Abbruscato, Vincent S. Hau, Terrence J. Gillespie, Joseph Zsigo, Victor J. Hruby and Thomas P. Davis
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 817-825;
Sarah A. Thomas
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Thomas J. Abbruscato
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Vincent S. Hau
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Terrence J. Gillespie
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Joseph Zsigo
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Victor J. Hruby
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Thomas P. Davis
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Abstract

[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; >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.

Footnotes

  • Send reprint requests to: Dr. Thomas P. Davis, Department of Pharmacology, University of Arizona, 1609 N. Warren St., Tucson, AZ 85724.

  • ↵1 This work was supported by NIDA DA-06284.

  • ↵2 Current address: Sherrington School of Physiology, UMDS St. Thomas Hospital Campus, Lambeth Palace Road, London SE1 7EH, United Kingdom.

  • Abbreviations:
    BBB
    blood-brain barrier
    BMEC
    brain microvessel endothelial cells
    PC
    permeability coefficient
    RP-HPLC
    reverse phase high-performance liquid chromatography
    k′
    capacity factor
    Abu
    α-aminobutyric acid
    HOBt
    N-hydroxybenzotriazole
    BOP
    benzotriazol-1-yl-oxy-tris-dimethylamino-phosphonium
    TFA
    trifluroacetic acid
    • Received October 15, 1996.
    • Accepted January 15, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherNEUROPHARMACOLOGY

Structure-Activity Relationships of a Series of [d-Ala2]Deltorphin I and II Analogues;in Vitro Blood-Brain Barrier Permeability and Stability

Sarah A. Thomas, Thomas J. Abbruscato, Vincent S. Hau, Terrence J. Gillespie, Joseph Zsigo, Victor J. Hruby and Thomas P. Davis
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 817-825;

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OtherNEUROPHARMACOLOGY

Structure-Activity Relationships of a Series of [d-Ala2]Deltorphin I and II Analogues;in Vitro Blood-Brain Barrier Permeability and Stability

Sarah A. Thomas, Thomas J. Abbruscato, Vincent S. Hau, Terrence J. Gillespie, Joseph Zsigo, Victor J. Hruby and Thomas P. Davis
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 817-825;
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