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Methoxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A AR antagonists for the potential treatment of neurological conditions.

ABSTRACT: A prior study reported on hydroxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A antagonists for the potential treatment of neurological conditions. A lead compound (1a) was identified with both A1 and A2A affinity in the micromolar range. The current study explored the structurally related methoxy substituted 2-benzylidene-1-indanone derivatives with various substitutions on ring A and B of the benzylidene indanone scaffold in order to enhance A1 and A2A affinity. This led to compounds with both A1 and A2A affinity in the nanomolar range, namely 2c (A1 K i (rat) = 41 nM; A2A K i (rat) = 97 nM) with C4-OCH3 substitution on ring A together with meta (3') hydroxy substitution on ring B and 2e (A1 K i (rat) = 42 nM; A2A K i (rat) = 78 nM) with C4-OCH3 substitution on ring A together with meta (3') and para (4') dihydroxy substitution on ring B. Additionally, 2c is an A1 antagonist. Consequently, the methoxy substituted 2-benzylidene-1-indanone scaffold is highly promising for the design of novel A1 and A2A antagonists.

SUBMITTER: Janse van Rensburg HD

PROVIDER: S-EPMC6390816 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Methoxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A AR antagonists for the potential treatment of neurological conditions.

Janse van Rensburg Helena D HD Legoabe Lesetja J LJ Terre'Blanche Gisella G Van der Walt Mietha M MM

MedChemComm 20190108 2

A prior study reported on hydroxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A antagonists for the potential treatment of neurological conditions. A lead compound (1a) was identified with both A1 and A2A affinity in the micromolar range. The current study explored the structurally related methoxy substituted 2-benzylidene-1-indanone derivatives with various substitutions on ring A and B of the benzylidene indanone scaffold i ...[more]

PMID: 30881617

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Project description:The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N(6)-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K(i) value of 0.66 microM. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-(phenylamino)-N(6)-cyclohexyladenine (12), 2-(phenylamino)-N(6)-cycloheptyladenine (19), and 2-phenylamino-N(6)-endo-norbornyladenine (21) as potent A(3) AR ligands with K(i) values of 51, 42, and 37 nM, respectively, with 30-200-fold selectivity in comparison to A(1) and A(2A) ARs. The most selective A(3) AR antagonist (>200-fold) was 2-(phenyloxy)-N(6)-cyclohexyladenine (22). 9-Methylation of 12, but not 19, was well-tolerated in A(3) AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-(phenylamino), 2-(phenyloxy), and 2-(phenylthio) substitutions, the order of affinity at the A(3) AR was oxy > or = amino > thio. Selected derivatives, including reversine (K(B) value of 466 nM via Schild analysis), competitively antagonized the functional effects of a selective A(3) AR agonist, i.e., inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N(6) position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A(3) AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation.

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Methoxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A AR antagonists for the potential treatment of neurological conditions.

Publications

Methoxy substituted 2-benzylidene-1-indanone derivatives as A<sub>1</sub> and/or A<sub>2A</sub> AR antagonists for the potential treatment of neurological conditions.

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