Some novel approaches to the design and synthesis of peptide–catecholamine conjugates

Abstract

SynopsisA series of novel, functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxyl group. Model amide derivatives have also been prepared in order to optimize the biological activity of these derivatives and also to aid in the design of appropriate peptides for the synthesis of conjugates. As a result of these studies, a series of amino acid and monodisperse peptide carriers, containing p-aminophenylalanine as the point of attachment for the drug, was prepared, together with the corresponding conjugates. In uitro and in uiuo evaluation of the congeners, model amides, and conjugates has demonstrated that the biological activity of these derivatives is extremely sensitive to structural modifications a t a point far-removed from the pharmacophore, in both the congener amide and conjugate series. A number of the model amides and conjugates have proven to he highly active when tested in both in uitro and in uiuo test systems. The implications of these results in terms of a novel structure-activity approach to drug design are discussed.

Conjugates of catecholamines. III. Synthesis and characterization of monodisperse oligopeptides conjugates related to isoproterenol

“…A novel series of p-aminophenylalanine-based peptide conjugates of previously-described N-carboxylic acid congeners of norepinephrine (9) has been prepared. The fact that the peptide carriers were completely monodisperse and varying in size from a single, blocked amino acid to pentapeptides has permitted complete characterization of the peptide carriers and conjugates.…”

“…p-Nitro-D-phenylalanine (6.20 g, 29.5 mmol) was acetylated with acetic anhydride (9 ml) in aqueous sodium hydroxide at pH 9 …”

Rapid identification of improved protein ligands using peptoid microarrays

“…Thousands of such microarrays can be made from a single OBOC library. 10 Thus, a single peptoid library could be used to couple with a large number of different lead molecules, providing a route the rapid isolation of higher affinity ligands for a large number of proteins. Such efforts are underway.…”

Pharmacokinetics and Excretion of Unique Beta-Adrenergic Agonists

“…Previous in vitro studies have shown that 119 and 143 are orders of magnitude more potent than ISO in the stimulation of cyclic adenosine monophosphate (cAMP) accumu lation in S49 mouse lymphoma cells [1][2][3][4][5] and that 143 is a more potent positive ino tropic agent than ISO as measured in an iso lated guinea pig atria preparation [2,5], In addition, in this preparation, 143 appeared to have preferential inotropic versus chrono tropic effects. The inotropic effect of 143 also persisted much longer than that ob served with ISO.…”

“…In vivo, 143 (i.v.) was shown to be more potent than ISO in the reduction of blood pressure in anesthetized rats [2][3][4][5], The ED50 values were found to be 1.44 X 10'9 mol/kg for 143 (0.78 pg/kg), 8.25 X 10'9 mol/kg for 119 (3.99 pg/kg), and 7.54 X 10-9 mol/kg for ISO (1.87 pg/ kg). Following intravenous administration to anesthetized dogs [4,5], the positive ino tropic response produced by 143 lasted 100 min, compared to the 2-3 min response observed with ISO at four times the molar dose.…”