Pharmaceutical Discovery Corporation

The United States of America As Represented by the Department of Health

R Tyler McCabe

Christopher A Rhodes

Kenneth Alan Jacobson

Solomon S Steiner

Brian R De Costa

Gregory S Shen

Phil Skolnick

Bryan R Wilson

Bruce F DeCosta

Muscarinic M.sub.2 receptor ligands are described which are suitable for the treatment of neurological disorders, and which may be administered with minimal side-effects. A method of synthesis of these compounds is also described.

M.sub.2 receptor ligand for the treatment of neurological disorders

Conjugates of fluorescent labels with specific, selective, and high affinity ligands for receptors have been synthesized and used to directly measure binding to receptors.

Fluorescent ligands

Drug delivery systems have been developed based on the formation of diketopiperazine (or analogs) microparticles. In the preferred embodiment the microparticle is stable at low pH and disintegrates at physiological pH, and is particularly useful for oral drug delivery. In other embodiments, the microparticles are stable at high pH and disintegrate at neutral or basic pH, or are stable at neutral pH and disintegrate at high or low pH. In the most preferred embodiment the microparticles are formed in the presence of the drug to be delivered, for example, insulin, felbamate, calcitonin or heparin. The diketopiperazine synthetic intermediates are preferably formed by cyclodimerization to form diketopiperazine derivatives at elevated temperatures under dehydrating conditions, functionalized on the side chains, and then precipitated with drug to be incorporated into microparticles.

Method for making self-assembling diketopiperazine drug delivery system

Conjugates of fluorescent labels with specific, selective, and high affinity ligands for receptors have been synthesized and used to directly measure binding to receptors. In the examples, fluorescein conjugates of the high-affinity benzodiazepine receptor ligands Ro 15-1788 and Ro 7-1986 were synthesized. The binding of these fluorescent ligands (BD 621, BD 623 and BD 607) to benzodiazepine receptors was characterized by direct fluorescence measurement. Both the equilibrium dissociation constants (K.sub.D) of BD 621 and BD 607 and the maximum number of binding sites (B.sub.max) estimated by fluorescence monitoring were consistent with values obtained by using radioligand binding techniques. The binding of BD 621 and BD 607 assessed by fluorescence measurement was reversible, abolished by photoaffinity labeling with Ro 15-4513, and unaffected by a variety of substances that do not bind to benzodiazepine receptors. The potencies of chemically diverse benzodiazepine receptor compounds to inhibit fluorescent ligand binding were highly correlated, with potencies obtained from radioligand binding techniques. These findings demonstrate that direct fluorescence measurement techniques can be used to quantitate ligand-receptor interactions.

Characterization of specific drug receptors with fluorescent ligands

The present invention is directed to compounds useful as probes for characterizing and studying the adenosine A.sub.2 receptor. The present invention is also directed to methods of treating central nervous system disorders and cardiovascular disorders which include treating hypertension and thrombosis by administering said compounds.

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South Salem, NY, United States of America

R Tyler McCabe