FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

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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 cogener" approach. The "carrier" molecule may be many times larger than the parent drug; indeed there is practically no maximum site limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow releases, the "functionalized cogener" 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 were developed as functionalized cogeners for adenosine receptors. Reporter groups such as fluorescent dyes have been covalently attached resulting in receptor probes of relatively high affinity. Sites for chain derivatization on the structures of telenzepine and pirenzepine (useful drugs in treating stomach ulcers and as research tools for the brain), two selective muscarinic antagonists, have been located. In a series of amino alkyl derivatives, it was found that increasing the chain length enhances the potency of the derivatives as a muscarinic antagonist. By incorporation of a phenyl isothiocyanate group, chemically reactive affinity labels for muscarinic receptors were developed. Other reporter groups included in the telenzepine series include biotin, p-aminophenylacetyl (for preparing radiotracers and photoaffinity labeling reagents), and fluorescent dyes fluorescein and tetramethylrhodamines (for locating the receptor sites microscopically and for binding assays that do not require the use of radioisotopes).