A functionalized congener approach to adenosine receptor antagonists: amino acid conjugates of 1,3-dipropylxanthine
1,3-Dipropyl-8-phenylxanthine, a synthetic analog of theophylline and a potent antagonist of adenosine at A1 and A2-adenosine receptors, has been attached covalently through a functionalized chain to amino acids and oligopeptides. The xanthine conjugates have been studied as competitive inhibitors o...
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Published in | Molecular pharmacology Vol. 29; no. 2; pp. 126 - 133 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.02.1986
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Subjects | |
Online Access | Get full text |
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Summary: | 1,3-Dipropyl-8-phenylxanthine, a synthetic analog of theophylline and a potent antagonist of adenosine at A1 and A2-adenosine
receptors, has been attached covalently through a functionalized chain to amino acids and oligopeptides. The xanthine conjugates
have been studied as competitive inhibitors of the specific binding of [3H]N6-cyclohexyladenosine to A1-receptors of rat cerebral
cortical membranes and for inhibition of cyclic AMP accumulation elicited by 2-chloroadenosine in guinea pig brain slices
through A2-receptors. A free amino group on the extended chain generally resulted in high potency at A1-receptors. The potency
(in some cases extending into the subnanomolar range) and selectivity for A1-receptors (up to 200-fold) suggest that this
approach can yield a versatile class of "functionalized congeners" of adenosine receptor antagonists in which distal modifications
of the attached moiety ("carrier") can serve also to improve pharmacodynamic and pharmacokinetic parameters. The water solubility
in many of the more potent analogs has been enhanced by two orders of magnitude over that of simple, uncharged 8-phenyl xanthine
derivatives. Analogs in which the carrier contains D-tyrosine have potential for development of iodinated radioligands for
adenosine receptors. The functionalized congener approach is potentially applicable to other drugs and for development of
prodrugs. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0026-895X 1521-0111 |