(E)-1-(Heterocyclyl or cyclohexyl)-2-[1,3,7-trisubstituted (xanthin-8-yl)] ethenes as A2a adenosine receptor antagonists

Giudice, Maria Rosaria Del; Borioni, Anna; Mustazza, Carlo; Gatta, Franco; Dionisotti, Silvio; Zocchi, Cristina; Ongini, Ennio

doi:10.1016/s0223-5234(96)80007-9

Cited by 21 publications

(14 citation statements)

References 23 publications

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“…24,25 Replacement of the styryl phenyl ring with a heterocyclic system as in the case of (E)-1,3-dipropyl-7-methyl-8-[2-(3-thienyl)ethenyl)]xanthine (DPMTX) (5) also produces a series of potent and selective A 2A antagonists. 107 Structure-activity relationship studies have shown that alkylation at N-7 of the xanthine and the trans geometry about the styryl double bond are structural features that are important for potent A 2A antagonism (Table 3). …”

Section: Methylxanthines As a 2a Antagonistsmentioning

confidence: 99%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Section: Methylxanthines As a 2a Antagonistsmentioning

confidence: 99%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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“…In particular (E)-KF 17837, (42, Fig. (7)) was potent in the nanomolar range at the A 2A AR and significantly selective against A 1 AR (62-fold, Table 2) [95,96]. Another compound, the 3-chlorostyrylcaffeine (CSC, 43, Fig.…”

Section: A 2a Ar Antagonists: Development and Structure-activity-relamentioning

confidence: 99%

A2A Receptor Ligands: Past, Present and Future Trends

Manera

Saccomanni²

2010

CTMC

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The adenosine A(2A) receptor is a member of the G protein-coupled receptor family and mediates multiple physiological effects of adenosine, both at the central nervous system and at peripheral tissues. Increasing evidence relates the A(2A) receptor with several pathological conditions such as neurodegenerative disorders, inflammation, pharmacological stress, and wound healing renewing the interest in A(2A) receptor agonists and antagonists as promising leads for drugs. However some of them initially tested in clinical trials presented several side effects, short half-life, lower solubility, and in some cases a lack of effects, perhaps attributable to receptor desensitization or to low receptor density in the targeted tissue. For these reasons it is evident that additional rational chemical modifications of the existing A(2A) receptor ligands to improve their affinity/selectivity and bioavailability as well as further studies to get new template for A(2A)AR ligands are necessary. The purpose of this review is to analyze and summarize the past and the present aspects related to the medicinal chemistry of A(2A) receptor ligands. Moreover their current and possible therapeutic applications have been also highlighted.

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“…[140] Furthermore, methyl substitutions at the 3 and 7 positions seem to be optimal for both affinity and selectivity at this receptor subtype ( Figure 3, Table 2). [120][121][122] Regarding the 8 position, the presence of an aromatic ring attached to an ethenyl group seems to be essential for both affinity and selectivity. [121][122][123] The bioisosteric replacement of phenyl ring with a thienyl moiety led to a DPMTX ((E)-1,3-dipropyl-7-methyl-8-[2-(3-thienyl)-ethenyl]xanthine, 41) which showed high affinity and selectivity.…”

Section: Xanthine Derivativesmentioning

confidence: 99%

“…[120][121][122] Regarding the 8 position, the presence of an aromatic ring attached to an ethenyl group seems to be essential for both affinity and selectivity. [121][122][123] The bioisosteric replacement of phenyl ring with a thienyl moiety led to a DPMTX ((E)-1,3-dipropyl-7-methyl-8-[2-(3-thienyl)-ethenyl]xanthine, 41) which showed high affinity and selectivity. [121] To overcome the problem of the photoisomerization, several derivatives in which the ethenyl group has been replaced with several constrained moieties such as 1-naphthyl (42) or racemic cyclopropyl (43) group have been synthesized, but a significant loss of potency and selectivity was observed.…”

Section: Xanthine Derivativesmentioning

confidence: 99%

“…[121][122][123] The bioisosteric replacement of phenyl ring with a thienyl moiety led to a DPMTX ((E)-1,3-dipropyl-7-methyl-8-[2-(3-thienyl)-ethenyl]xanthine, 41) which showed high affinity and selectivity. [121] To overcome the problem of the photoisomerization, several derivatives in which the ethenyl group has been replaced with several constrained moieties such as 1-naphthyl (42) or racemic cyclopropyl (43) group have been synthesized, but a significant loss of potency and selectivity was observed. [124] Two different approaches have been used aimed at improving the water solubility of styryl xanthines: introduction of polar groups on the phenyl ring, or preparation of phosphate prodrugs.…”

Section: Xanthine Derivativesmentioning

confidence: 99%

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Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

et al. 2007

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Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.

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(E)-1-(Heterocyclyl or cyclohexyl)-2-[1,3,7-trisubstituted (xanthin-8-yl)] ethenes as A2a adenosine receptor antagonists

Cited by 21 publications

References 23 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

A2A Receptor Ligands: Past, Present and Future Trends

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

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(E)-1-(Heterocyclyl or cyclohexyl)-2-[1,3,7-trisubstituted (xanthin-8-yl)] ethenes as A2a adenosine receptor antagonists

Cited by 21 publications

References 23 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

A2A Receptor Ligands: Past, Present and Future Trends

Highlights on the Development of A2A Adenosine Receptor Agonists and Antagonists

Contact Info

Product

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Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists