title: Structure-activity relationships of a series of [D-Ala2]deltorphin I and II analogues; in vitro blood-brain barrier permeability and stability.
abstract: [D-Ala2]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-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., t 1/2 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; x10(-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 prodrug, 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.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Thomas
authors.forename: T J
authors.initials: TJ
authors.lastname: Abbruscato
authors.forename: V S
authors.initials: VS
authors.lastname: Hau
authors.forename: T J
authors.initials: TJ
authors.lastname: Gillespie
authors.forename: J
authors.initials: J
authors.lastname: Zsigo
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: T P
authors.initials: TP
authors.lastname: Davis
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier; D002417:Cattle; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012008:Recurrence; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; C060208:deltorphin I, Ala(2)-; C060209:deltorphin II, Ala(2)-