Structure-Activity Relationships of N6-Benzyladenosine-5'-uronamides as A3-Selective Adenosine Agonists

Gallo‐Rodriguez, Carola; Xd, Ji; Melman, Neli; Bd, Siegman; Lh, Sanders; Orlina, J; Fischer, Bilha; Pu, Qiaosheng; Me, Olah; Pj, van Galen

doi:10.1021/jm00031a014

Cited by 221 publications

(223 citation statements)

References 24 publications

(88 reference statements)

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“…Thus, both 11 and 14 are potent and selective agonists for the A 3 AR. This finding extended our previous observation that N 6 -iodobenzyl group is optimal for A 3 AR affinity and selectivity [25]. However, it should be noted that the N 6 -methyl group is somewhat detrimental to the binding affinity at the rat A 3 AR.…”

Section: Discussionsupporting

confidence: 87%

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: Discussionsupporting

confidence: 87%

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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“…Compounds 7a and 9a were synthesized as described. 25,26 Proton nuclear magnetic resonance spectroscopy was performed on a Varian GEMINI-300 spectrometer, and all spectra were obtained in CDCl 3 . Chemical shifts (δ) relative to tetramethylsilane are given.…”

Section: Discussionmentioning

confidence: 99%

“…25,27 The more synthetically challenging (S)-isomer (5d) was available only as the racemate and therefore was tested as such. 23 At rat A 1 , rat A 2A , and human A 3 subtypes, the (N)-analogue proved to be of much higher affinity than the (S)-analogue.…”

Section: Biological Activitymentioning

confidence: 99%

“…1,26 The 2-chloro substitution of compound 8c could also be removed by catalytic reduction to give 6c. An N 6 -(3-iodobenzyl) group was introduced in either aristeromycin, 5b, or (N)-methanocarbaadenosine, 5c, by the Dimroth rearrangement, 25 to give 7b (Scheme 2) and 7c (Scheme 1). A sample of the antipodal (S)-methanocarba-adenosine, 5d, was synthesized in racemic form by Marquez and co-workers by an intramolecular carbene addition reaction.…”

Section: Chemical Synthesismentioning

confidence: 99%

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Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A 1 and A 3 receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A 1 , A 2A , and A 3 receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A 3 receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N 6 -substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A 1 or A 3 receptors, respectively, were synthesized. The N 6 -cyclopentyl derivatives were A 1 receptor-selective and maintained high efficacy at recombinant human but not rat brain A 1 receptors, as indicated by stimulation of binding of [ 35 S]GTP-γ-S. The (N)-methanocarba-N 6 -(3-iodobenzyl)adenosine and its 2-chloro derivative had K i values of 4.1 and 2.2 nM at A 3 receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A 3 receptors (EC 50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y 1 receptors, at least three adenosine receptors favor the ribose (N)-conformation.In work designed to develop potent and selective agents, the structure-activity relationships of adenosine derivatives as ligands (principally agonists) at the four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been explored extensively. Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).* Address correspondence to Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: (301) In general, for adenosine agonists, numerous modifications of the N 6 -position with cycloalkyl and other hydrophobic moieties provide selectivity for A 1 receptors, although the affinities of these N 6 -substituted adenosine derivatives (e.g. N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists. An intact f...

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“…A protective e ect following A 3 receptor stimulation at the cardiac level has been described in di erent animal models (Strickler et al, 1996;Stambaugh et al, 1997;Tracey et al, 1997) but the lack of any signi®cant e ect of the A 3 selective agonist IB-MECA (Gallo-Rodriguez et al, 1994) suggests that an A 3 -mediated in¯uence of adenosine on cardiac function can be excluded.…”

Section: Discussionmentioning

confidence: 99%

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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1 Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic e ect at the highest doses. The ®rst phase hypotensive response was signi®cantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2 The A 2a /A 2b agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not signi®cantly modi®ed by the A 2b antagonist enprofylline. 3 The A 2a agonist CGS 21680 did not signi®cantly in¯uence basal HR while induced a hypotensive response antagonized by the A 2a selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4 The A 1 agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A 1 selective antagonist DPCPX signi®cantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5 The A 1 /A 3 agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a signi®cant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6 The selective A 3 agonist IB-MECA revealed a weak hypotensive and bradycardic e ect, but only at the highest doses. 7 In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A 2a -and NO-mediated hypotension, and a bradycardic e ect with a consequent hypotension, via atypical A 1 receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A 3 receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed. IntroductionFour classes of membrane surface adenosine receptors are described, de®ned A 1 , A 2a , A 2b and A 3 , through which the nucleoside in¯uences many functions in humans and other animals (Ralevic & Burnstock, 1998). As far as the cardiovascular system is concerned, adenosine slows heart rate (HR) and atrioventricular conduction and antagonizes the cardio-stimulatory e ects of catecholamines via cardiac A 1 receptors in di erent mammals (Belardinelli et al., 1989;Olsson & Pearson, 1990). An increase in blood pressure (BP) and HR has been described in rats and in cats via central A 1 receptors (St Lambert et al., 1994; SilvaCarvalho et al., 1993). In contrast, a dose-related decrease in BP and HR is observed after microinjection of adenosine into the caudal nucleus of tractus solitarii in the rat (Lo et al., 1998).As regards a direct e ect on blood vessels, A 1 purinoceptors mediate vasodilation in the porcine coronary artery (Merkel et al., 1992) but they are involved, on the contrary, in vasoconstrictor responses, i.e. in the rat kidney (Jackson, 1991), in guinea-pig pulmonary artery and aorta (Biaggioni et al., 1989;Stoggall & Shaw, 1990) and in hamster skin (Stojanov & Proctor, 1990;Proctor & Stojanov, 1991).Moreover, a signi®cant role of A 1 receptors in the regulation of BP also appears to be linked to a prejunction...

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Structure-Activity Relationships of N6-Benzyladenosine-5'-uronamides as A3-Selective Adenosine Agonists

Cited by 221 publications

References 24 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

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

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