Brush-border-enzyme-mediated intestine-specific drug delivery. Amino acid prodrugs of 5-aminosalicylic acid.

5-Aminosalicylic acid (5-ASA) is the active principle of a number of preparations aimed at the treatment of inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, but its efficacy is limited by early absorption and metabolism. The possibility to exploit the selective hydrolytic activity of brush border enzymes such as aminopeptidase A and carboxypeptidases was studied by preparing the following four amino acid prodrugs of 5-ASA: 5-(N-L-aspartylamino)-2-salicylic acid, disodium salt (18), 5-(N-L-glutamylamino)-2-salicylic acid, disodium salt (19), [(5-aminosalicyl)-L-prolyl]-L-leucine, sodium salt (25), and [[5-(N-L-glutamylamino)salicyl]-L-prolyl]-L-leucine, disodium salt (28). In these compounds, the peptide bond is selectively split by the intestinal brush border aminopeptidase A (compounds 18, 19, and 28) and carboxypeptidases (compounds 25 and 28).

Persistent binding of fatty acyl derivatives of naltrexamine to opioid receptors.

A series of fatty acid derivatives of naltrexamine and naltrexhydrazine were synthesized and evaluated for their persistent binding to opioid receptors. Members of this series were found to require greater than five washes for removal from mouse brain membranes when the fatty acyl chain was saturated. The presence of unsaturation in the fatty acyl groups enhanced the persistent binding.

Role of the spacer in conferring kappa opioid receptor selectivity to bivalent ligands related to norbinaltorphimine.

The thiophene 2 and pyran 3 analogues of the kappa-selective opioid antagonist norbinaltorphimine (1a, norBNI) were synthesized and tested in an effort to determine the contribution of the spacer to the interaction of bivalent ligands at different opioid receptor types. Both 2 and 3 were found to be selective kappa opioid receptor antagonists in smooth muscle preparations, and they bound selectively to kappa-recognition sites. The thiophene analogue 2 displayed binding selectivity that was of the same order of magnitude as that of 1a, while 3 was considerably less selective for kappa site.

Transfer of fatty acyl groups from membrane phosphatides to opiate ligands.

Investigation of the persistent opioid receptor binding of hydrazine-containing opiate ligands to brain membranes has revealed that it is related to conversion of these ligands to fatty acylhydrazone or fatty acylhydrazide derivatives. The fatty acyl group was found to be derived from membrane phosphatides. Persistent binding does not occur when this pool of phosphatides is removed by extensive washing, and it is restored upon addition of phosphatide to the membranes.

A lymphotropic prodrug of L-dopa: synthesis, pharmacological properties, and pharmacokinetic behavior of 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)prop anoyl] propane-1,2,3-triol.

A glyceride derivative of L-Dopa, 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propan oyl] propane-1,2,3-triol (1), was synthesized and tested as an orally administrable prodrug endowed with lymphotropic properties. In the oxotremorine and reserpine tests, 1 exhibited an anti-Parkinsonian activity of longer duration than L-Dopa. The time course of concentration of 1 in the intestinal lymph of rat was determined and compared to that of L-Dopa.