N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine and its uronamide derivatives. Novel adenosine agonists with both high affinity and high selectivity for the adenosine A2 receptor

Bridges, Alexander J.; Bruns, Robert F.; Ortwine, Daniel F.; Priebe, Steven R.; Szotek, Deedee L.; Trivedi, Bharat K.

doi:10.1021/jm00402a004

Cited by 79 publications

(38 citation statements)

References 2 publications

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“…For example, 2-chloro-R-PIA was a partial A 3 AR agonist, and CCPA was an antagonist. The N 6 -derivative DPMA, a potent A 2A AR agonist [24], was also demonstrated to be a moderately potent antagonist at the A 3 AR [10]. In the present study, the newly synthesized adenosine derivative 16 was demonstrated to be a potent antagonist for human A 3 AR.…”

Section: Discussionmentioning

confidence: 53%

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

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We have found previously that structural features of adenosine derivatives, particularly at the N 6 -and 2-positions of adenine, determine the intrinsic efficacy as A 3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A 3 AR expressed in CHO cells. Both 2′-and 3′-hydroxyl groups in the ribose moiety contribute to A 3 AR binding and activation, with 2′-OH being more essential. Thus, the 2′-fluoro substitution eliminated both binding and activation, while a 3′-fluoro substitution led to only a partial reduction of potency and efficacy at the A 3 AR. A 5′-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3′-fluoro derivatives. The 4′-thio substitution, which generally enhanced A 3 AR potency and selectivity, resulted in 5′-CH 2 OH analogues (10 and 12) which were partial agonists of the A 3 AR. Interestingly, the shifting of the N 6 -(3-iodobenzyl)adenine moiety from the 1′-to 4′-position had a minor influence on A 3 AR selectivity, but transformed 15 into a potent antagonist (16) (K i = 4.3 nM). Compound 16 antagonized human A 3 AR agonist-induced inhibition of cyclic AMP with a K B value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A 3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A 3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A 3 ARs.

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Section: Discussionmentioning

confidence: 53%

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

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“…The selective agonist ATL-146e has much greater affinity for the A 2A AR than CGS21680 45 . Although most N 6 -substituted adenosine agonists are A 1 AR-or A 3 AR-selective, the agonist DPMA (diastereomeric pair) is more than 30-fold selective for the rat A 2A AR compared with the rat A 1 AR and A 3 AR subtypes, but has similar affinity at human A 1 , A 2A and A 3 ARs 43,46 .…”

Section: A 2a Arsmentioning

confidence: 99%

“…ZM241,385 and SCH 58261 are highly potent and selective A 2A AR antagonists 47,48 , although ZM241,385 has been shown to bind with intermediate affinity at the human A 2B AR 46,47 . The phenolic group of ZM241,385 can be radio-iodinated to provide an A 2A AR-selective radioligand 49 .…”

Section: A 2a Arsmentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,289

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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“…One of the most significant efforts in the medicinal chemistry of adenosine derivatives was that of Parke-Davis in the 1980s [10,[20][21][22][23]. This program encompassed both agonist and antagonist pharmacophores for adenosine receptors and resulted in the identification of several classes of N 6 -substituted adenosine derivatives.…”

Section: Adenosine Agonistsmentioning

confidence: 99%

“…The majority of these were A 1 selective, but others including CI-936 [N 6 -(2,2-diphenylethyl)adenosine, 7] [10] were potent agonists at A 2 -adenosine receptors. Continued efforts to optimize the A 2 affinity of this series of compounds resulted in a series of substituted diphenyl-ethyladenosine derivatives, from which DPMA (N 6 -[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine, PD 125,944, 8) was identified as having a 32-fold selectivity for the A 2 receptor, with a K i value of 4.4 nM [21].…”

Section: Adenosine Agonistsmentioning

confidence: 99%

Novel therapeutics acting via purine receptors

Jacobson

Trivedi²,

Churchill

et al. 1991

Biochemical Pharmacology

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A recent conference entitled Purines in Cell Signalling: Targets for New Drugs, held in Rockville, Maryland, in September, 1989, was one indication of the increasing interest in developing agonists and antagonists of P 1 -(adenosine) and P 2 -(ATP) purinoceptors [1] as potential therapeutic agents. Extracellular adenosine, acting at its membrane bound A 1 and A 2 receptors, is a ubiquitous modulator of cellular activity. The purine can arise from several sources including ATP hydrolysis by ectokinase activity in the region of the nerve terminal [2] and from S-adenosylhomocysteine [3] and ATP within the cell. Together with its more stable analogs, adenosine is a potent inhibitor of neurotransmitter release in both the central and peripheral nervous systems, and in cardiac, adipose and other tissues. Adenosine can also affect blood pressure and heart rate as well as modulate the function of the immune, inflammatory, gastrointestinal, renal and pulmonary systems, either via its effects on transmitter release or directly via receptor mechanisms altering intracellular transduction processes.

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N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine and its uronamide derivatives. Novel adenosine agonists with both high affinity and high selectivity for the adenosine A2 receptor

Cited by 79 publications

References 2 publications

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Adenosine receptors as therapeutic targets

Novel therapeutics acting via purine receptors

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