Synthesis and evaluation of the physicochemical properties of esterase-sensitive cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid linkers.
In an attempt to improve the membrane permeabilities of opioid peptides, we have synthesized cyclic prodrugs of [Leu5]-enkephalin and DADLE using a coumarinic acid or a phenylpropionic acid linker. The synthesis of the coumarinic acid- and phenylpropionic acid-based cyclic prodrugs followed similar strategies. Key intermediates were the compounds with the C-terminal amino acids of opioid peptides (L-Leu, [Leu5]-enkephalin; D-Leu, DADLE) attached to the phenol hydroxyl group and the remaining amino acids of the peptide linked via the N-terminal amino acid (L-Tyr) attached to the carboxylic acid groups of the prodrug moieties (coumarinic acid or propionic acid). Cyclization of these linear precursors gave the cyclic prodrugs in 30-50% yields. These cyclic prodrugs exhibited excellent transcellular permeation characteristics across Caco-2 cell monolayers, an in vitro model of the intestinal mucosa. To correlate the cellular permeabilities of these cyclic prodrugs with their physicochemical properties, we calculated their Stokes-Einstein molecular radii from their diffusion coefficients which were determined by NMR and we determined their membrane interaction potentials using immobilized artificial membrane (IAM) column chromatography. The cyclic prodrugs exhibited molecular radii similar to those of the parent compounds, [Leu5]-enkephalin and DADLE. However, these cyclic prodrugs were shown to have much higher membrane interaction potentials than their corresponding opioid peptides. Therefore, the enhanced cellular permeation of the cyclic prodrugs is apparently due to the alteration of their lipophilicity and hydrogen bonding potential, but not their molecular sizes.
Department of Chemistry, North Carolina State University, Raleigh 27695-8204, USA. binghe_wang@ncsu.edu
B
B
Wang
K
K
Nimkar
W
W
Wang
H
H
Zhang
D
D
Shan
O
O
Gudmundsson
S
S
Gangwar
T
T
Siahaan
R T
RT
Borchardt
D000595:Amino Acid Sequence; D002463:Cell Membrane Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003373:Coumaric Acids / Q000737:chemistry; D004743:Enkephalin, Leucine / Q000737:chemistry / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000737:chemistry / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism; D008567:Membranes, Artificial; D008954:Models, Biological; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010539:Permeability; D010666:Phenylpropionates / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D003373:Coumaric Acids; D008567:Membranes, Artificial; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D010666:Phenylpropionates; D011355:Prodrugs; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D004950:Esterases