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

• Published in: The Journal of pharmacology and experimental therapeutics 1997-05, Vol.281 (2), p.817-825
• Main Authors: Thomas, S A, Abbruscato, T J, Hau, V S, Gillespie, T J, Zsigo, J, Hruby, V J, Davis, T P
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - pharmacology; Animals; Blood-Brain Barrier; Cattle; Half-Life; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Recurrence; Structure-Activity Relationship
• ISSN: 0022-3565; 1521-0103

[ d -Ala 2 ]deltorphins are enzymatically stable, amphibian heptapeptides that have a higher affinity and selectivity for delta -opioid receptors than any endogenous mammalian compound known. This study investigated the in vitro blood-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 -Ala 2 ]deltorphin I, [ d -Ala 2 ]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 -Ala 2 ]deltorphin I; >15 hr- [ d -Ala 2 ,Ser 4 , d -Ala 5 ]deltorphin. Although, no analogue was found to increase the BBB permeability coefficient (PC; ×10 −4 cm/min) of the parent compounds ([ d -Ala 2 ]deltorphin II, PC = 23.49 ± 2.42) analogues were identified: [Arg 0 , d -Ala 2 ]deltorphin II, PC = 19.06 ± 3.73 and [Pro −1 ,Pro 0 , d -Ala 2 ]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.