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Investigation on 2',3'-O-Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists.

ABSTRACT: Antagonists of the purinergic P2X3 receptors represent promising drugs for the treatment of inflammation and pain. The ATP derivative 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) has been described as a potent competitive inhibitor of this receptor. In this work, the design and synthesis of novel TNP-ATP analogues bearing alkyl groups in the 2',3'-position are reported. These compounds were biologically evaluated as P2X3 antagonists using the patch clamp recording technique on mouse trigeminal ganglionic sensory neurons. Some of the compounds showed nanomolar inhibitory potency for the P2X3 receptor. Further modification of these derivatives was made by substitution of the triphosphate chain with different acidic groups. All compounds were additionally tested at five human P2X receptor subtypes stably expressed in 1321N1 astrocytoma cells to evaluate their potency and P2X3 selectivity. Results confirmed the P2X3 antagonist potency for some derivatives.

SUBMITTER: Dal Ben D

PROVIDER: S-EPMC6466514 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Investigation on 2',3'-<i>O</i>-Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists.

Dal Ben Diego D Buccioni Michela M Lambertucci Catia C Marucci Gabriella G Spinaci Andrea A Marchenkova Anna A Abdelrahman Aliaa A Nistri Andrea A Müller Christa E CE Volpini Rosaria R

ACS medicinal chemistry letters 20181226 4

Antagonists of the purinergic P2X3 receptors represent promising drugs for the treatment of inflammation and pain. The ATP derivative 2',3'-<i>O</i>-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) has been described as a potent competitive inhibitor of this receptor. In this work, the design and synthesis of novel TNP-ATP analogues bearing alkyl groups in the 2',3'-position are reported. These compounds were biologically evaluated as P2X3 antagonists using the patch clamp recording technique on mouse trige ...[more]

PMID: 30996785

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Project description:As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11?-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11?-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11?-aryl estradiol analogs or their potential as scaffolds for drug conjugation.We prepared and characterized a series of 11?-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ER?-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists.The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ER?-LBD, ranging from 13-83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11?-substituent than upon the nature of the terminal groupWe have developed a synthetic strategy that provides facile access to potent 11?-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER?-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11?-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11?-aryl estradiol analogs as potential drug delivery systems and imaging agents.

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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Investigation on 2',3'-O-Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists.

Publications

Investigation on 2',3'-<i>O</i>-Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists.

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