Chemical and Biological Aspects of Peptide Catecholamine Conjugates

Polymeric derivatives of D-isoproterenol have been prepared by diazotization to water-soluble, random copolypeptides of hydroxypropylglutamine and p-aminophenylalanine, molecular weight 1500, 3000, and 9600. The polymeric isoproterenol derivatives were purified by gel chromatography which reduced contamination by the parent catecholamine to undetectable levels (i. e., less than 0.01 wt %) and by 6-aminoisoproterenol (a possible decomposition product) to less than 0.4%. The derivatives were found to elicit positive chronotropic responses in isolated perfused guinea pig hearts, with mean effective doses (ED₅₀) which were between 1.3 and 2.0 orders of magnitude (for the 1500 and 9600 molecular weight derivatives, respectively) less than the ED50 for D-isoproterenol. Inotropic response decay times in isolated cat papillary muscles following washouts suggest that the polymer-bound drug does not diffuse into muscle tissues. In vivo biological studies (in conscious dogs) indicate that the polymeric drugs have significantly prolonged durations of action of between 5.5 ± 0.4 min for the derivative of highest (9600) molecular weight and 27.4 ± 4.9 min for the derivative of lowest (1500) molecular weight compared with 4.5 ± 0.14 min for a comparable dose of free isoproterenol. Possible explanations for the inverse relationship between the molecular weights of the derivatives and their in vivo durations of action are suggested. Our findings demonstrate that under controlled conditions isoproterenol can retain biological activity while covalently bound to a soluble polymeric support. The in vivo biological data suggest that the tethering of drugs to polymers may provide a means of maximizing the therapeutic utility of drugs with short half-lives.