Recent work in our laboratory has demonstrated that certain drugs may be attached to well-defined """"""""carrier"""""""" molecules and still retain the ability to bind to the receptor site and effect biological activity. This synthetic strategy for the attachment of drugs to carriers is termed the """"""""functionalized congener"""""""" approach. The """"""""carrier"""""""" molecule may be many times larger than the parent drug; indeed there is practically no maximum size limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow release, the """"""""functionalized congener"""""""" approach is designed to produce analogs for which no metabolic cleavage step is necessary for activation. Moreover, the attachment of the drug to a """"""""carrier"""""""" such as a peptide may result in enhanced affinity at an extracellular receptor site and an improvement in the pharmacological profile of the parent drug. Purine derivatives containing attached chains have been developed as functionalized congeners that either activate or antagonize adenosine receptors, and a similar strategy has been used for ATP receptors. For example, the 2-position of the purine moiety has been identified for attachment of functionalized chains in ATP derivatives as P2X and P2Y receptor agonists. Reporter groups such as fluorescent dyes have been covalently attached resulting in receptor probes of relatively high affinity. A3 adenosine receptors are important in the regulation of CNS, cardiac, inflammatory; and reproductive functions. We have developed the first selective agents for this novel receptor. Selective A3 agonists are effective in the treatment of neuro-degenerative diseases. Antagonists have been proposed to have anti-inflammatory properties. New xanthine and adenosine derivatives are being synthesized, screened for A3- receptor selectivity, and later tested in vivo. We have found flavonoids and dihydropyridines to be suitable structural leads for antagonists at human A3 receptors. Chemical modification of these leads (using a template approach) has resulted in compounds with >37,000-fold selectivity. Site-directed mutagenesis and molecular modeling have been used to characterize the ligand binding site of the A3 receptor to predict which regions of a given ligand may be amenable to a chain attachment approach. We have designed and synthesized functionalized congeners to act as potent antagonists of the P2X7 ion channels. This receptor is found in macrophages and plays a role in inflammation both in the periphery and in the central nervous system. These antagonists are derivatives of tyrosine, and the application of standard methods of peptide chemistry allows us to explore the geometry of the binding site on the receptor. Amine functionalized congeners in which a reactive chain forms an extension of the Tyr side chain have been identified. Since the receptor likely consists of higher order bundles of multiple subunits, and we might expect more that one binding site for agonists or for antagonists to occur on each functional ion channel, we have designed dimers of these antagonists that still act as potent blockers of the actions of ATP.
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