Roberto P. Rosenkranz

Autacoids as modulators of the inflammatory and immune response

Once considered only mediators of inflammation, autacoids, (histamine, prostaglandins and beta-mimetic catecholamines) have been found to be generated during specific early and late phases of immunity. They need sufficient concentrations to affect immunocytes and can modulate immunity usually by inhibiting it. Receptors for the autacoids on the immunocytes are nonrandomly distributed. A small portion of T suppressor cells always appear to have receptors on them, but precursor B cells and precursors of T cells that produce lymphokines or are responsible for cytolysis do not. Instead, as these cells mature they develop their autacoid receptors. With one exception, the function of the immunocytes is inhibited by the effects of autacoids. Again, in all but one instance, that inhibitory modulating effect is mediated by and directly proportional to the intracellular concentrations of cyclic adenosine monophosphate (AMP) generated by the autacoid. The clinical implications of these observations are beginning to be appreciated. One of them is that pharmacologic antagonists of the autacoids can have predictable but hitherto unanticipated effects on immune functions. It is inconceivable that these effects will not have clinical value.

In vitro pharmacologic activity of congener derivatives and model conjugates of propranolol and practolol.

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.

Autacoids for Immune Modulation: a Strategy

ABSTRACT Autacoids have been found to be both mediators and modulators of rather complex in vitro and in vivo models of inflammation and immunity. Their eventual use as therapeutic modulators of these processes depends on a precise definition of their role in the subsets of cells that participate in the diseases. Defining this in turn depends on production of higher potency congeners of autacoids that also might be tissue directed. This report summarizes the strategy that has led to high potency congeners of catecholamines; it shows some evidence of the congeners tissue selectivity and early evidence of enhancing the latter by making conjugates of the congeners. The conjugates with dipeptide carriers have unexpected properties and may be the precursors of conjugates whose carrier moieties are monoclonal antibodies and, thereby, become organ directed.

Application of the Congener Approach to the Design and Synthesis of Peptide-Catecholamine Conjugates

The potential for increasing the therapeutic index of drugs through covalent attachment to natural or synthetic macromolecules was first demonstrated almost 30 years ago.1 Since that time, a wide variety of both drugs and polymeric carriers has been studied in this context.2–4 However, these studies have failed to result in a generalized understanding of the factors which are important for optimization of the design of polymeric drug conjugates. This may be attributable, in part at least, to the fact that the vast majority of carriers studied have been high molecular weight and also polydisperse. Characterization of the polymer-drug conjugates --both chemical and biological --; is therefore difficult. Correlations between the properties of the carrier and the resultant conjugate are often impossible.