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

The United States of America as Represented by the Secretary of

Kenneth L Kirk

Kenneth Alan Jacobson

John W Daly

Markku I Linnoila

David Hebel

Thomas Miller

Robert Phillips

Kazunori Mine

David C Furlano

Yechiel Shai

This invention comprises a series of N.sup.6 -substituted adenosine analogues bearing functionalized chains for the covalent attachment to probes or solid supports. In these compounds coronary vasodilation in the open thorax dog model, typical of A.sub.2 -adenosine receptor agonists, is shown. The potency is modulated by distal structural changes in the chain, with the highest A.sub.2 -potency observed for two methylamides, a primary amine congener, and a biotin conjugate. These compounds have antihypertensive activity and certain components are charged and are excluded from crossing the blood-brain barrier.

Adenosine functionalized congeners as cardiovascular treating agents for

Azido-substituted aromatic amino acids represented by the following formula I are synthesized through the use of tyrosine phenol-lyase. The azido derivatives are suitable for use as photoaffinity labels and inhibitors; ##STR1## wherein R.sup.1 represents a lower alkyl, a lower alkoxy, or an hydroxy group; R.sup.2 and R.sup.3 each independently represent a hydrogen or a lower alkyl group; X represents a hydrogen, a lower alkyl, an alkali metal, or an ammonium group; n is an integer of 0 to 3.

Azido-substituted aromatic amino acids

This application discloses probes for adenosine receptors which are functionalized congeners of the following compound: ##STR1## wherein R is --CH.sub.2 --C(O)--R' or ##STR2## These probes bind to A.sub.2 and A.sub.3 adenosine receptors and aid in quantifying and characterizing the receptors. The compounds may be labeled, for example with fluorescent compounds or radioactive compounds, or unlabeled.

Molecular probes for adenosine receptors

Radioactive fluorine can be easily introduced into biologically active molecules containing amino groups. A p-bromomethyl benzoyl group is coupled to the amino group of the biologically active molecule, and bromine is displaced by fluorine. Alternatively, the bromine on the bromomethylbenzoyl group is first displaced by fluorine, and the fluoromethyl benzoyl group is then coupled to the amino group of the biologically active molecule. The compounds so produced are useful in diagnostic nuclear medicine.

Process for introducing fluorine into biologically active materials

A functionalized congener approach to drugs acting at A.sub.1 and A.sub.2 adenosine receptor types is applicable to prodrug design. The prodrugs affect a more efficient delivery of the drug at the particular site of the body affected and take advantage of selective biochemical cleavages and alteration in distribution characteristics. In particular, kidney functions and lipid functions are stressed in the invention.

Adenosine receptor prodrugs

Primary and secondary amines in biological fluids are selectively derivitized by reaction with esters of N-hydroxysuccinimide or N-hydroxysulfosuccinimide to form an N-acylated derivative. Those N-acylated derivatives may then be extracted into a polar organic phase and extracted. Non-electroactive amines may be made suitable for coulometric analysis by selecting the ester used so as to attach an electroactive group to the amine. For example, histamine may be reacted with the Bolton-Hunter reagent to form a suitable derivative in high yield.

Derivatization of amines for electrochemical detection

Certain functionalized cogeners of 1,3-dialkylxanthine exhibit high potency and selectivity as antagonists for A.sub.1 - and A.sub.2 -adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl at the 8 position para-substituted with a functionalized chain to provide high water solubility and high receptor affinity. Some of these analogs, containing a distal amino- or carboxylic-functionalized chain, are suitable for synthesis of amino acid conjugates. The compounds of this invention are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants, and diuretics.

Biologically-active xanthine derivatives

Certain functionalized congeners of 1,3-dialkylxanthine exhibit high potency and selectivity as antagonists for A.sub.1 - and A.sub.2 -adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl at the 8 position para-substituted with a functionalized chain to provide high water solubility and high receptor affinity to such an extent that these compounds are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants, and diuretics.

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Bethesda, MD, United States of America

Kenneth L Kirk