CONJUGATED VASOACTIVE AGENTS AS A NEW CLASS OF DRUGS

特别是一些心血管药物的临床应用

The clinical utility of a number of cardiovascular drugs particularly vasoactive amines, is limited by their widespread distribution and effects. In the last two years, we have extended preliminary observations made by ourselves and others that congeners and congener derivatives of betamimetic catecholamines and beta blockers can be synthesized to serve as pharmacophores for covalent linkage to uniform peptide or protein carriers to construct fully pharmacologically and chemically characterizable drug conjugates. The congeners, congener derivatives and conjugates may be more potent, more efficacious and longer acting in vitro and in vivo than the parent drug. They may have apparent receptor and tissue specific effects that differ in key physical and pharmacological ways from the parent. Furthermore, they may be active when given by routes (e.g., oral administration) which were ineffective for the parent compounds. Based on these phenomenologic observations, we propose to: 1) study the mechanisms (molecular, physical, chemical, pharmacologic, metabolic and/or pharmacokinetic) that explain the variant effects of parent compounds from key congeners and/or conjugates and the variant effects seen in vitro versus in vivo by the same compound; 2) economically determine the changes in potency and efficacy of further systematic chemical alterations of the conjugates; 3) determine whether oligopeptide, monoclonal antibody or other monodisperse protein carriers, linked to different combinations of pharmacophores, can be key determinants of tissue and/or receptor specific events caused by the conjugates; and 4) continue to make compounds available for others interested in the use of these agents as probes to understand the molecular mechanisms of drug effects in tissues or who wish to capitalize on the apparent or real tissue or effect specificity already seen in two chemicals that make them very suitable as potential drugs for man.