Structure-Activity Relationships of Adenosine A1 and A2 Receptors

Trivedi, Bharat K.; Bridges, Alexander J.; Bruns, Robert F.

doi:10.1007/978-1-4612-4504-9_3

Cited by 26 publications

(26 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Adenosine has several sites that can potentially interact with receptor amino acids (8). The adenine group contains five nitrogen atoms (N N 7 , and N 9 ) that can interact with receptor sites, whereas the ribose moiety contains three hydroxyl groups (2Ј, 3Ј, 5Ј) (8).…”

Section: Methodsmentioning

confidence: 99%

“…The adenine group contains five nitrogen atoms (N N 7 , and N 9 ) that can interact with receptor sites, whereas the ribose moiety contains three hydroxyl groups (2Ј, 3Ј, 5Ј) (8). Within the adenine group, removal of either of the N 6 , N 7 , and N 9 nitrogen atoms results in more than a 1000-fold loss in affinity for A 1 ARs (8).…”

Section: Methodsmentioning

confidence: 99%

“…Within the adenine group, removal of either of the N 6 , N 7 , and N 9 nitrogen atoms results in more than a 1000-fold loss in affinity for A 1 ARs (8). Removal of the N 1 and N 3 nitrogen molecules results in 10-and 100-fold reductions in affinity for A 1 ARs, respectively (8). The three ribose-hydroxyl groups also are very important for binding, as removal of these groups results in significant reduction in the affinity for A 1 ARs (8).…”

Section: Methodsmentioning

confidence: 99%

“…Because modification of the N 6 adenine position confers A 1 AR selectivity of adenosinergic compounds (8), this observation strongly suggests that the N 6 -adenine position interacts with sites within TMs 1-4 (7). Within the first four TM domains of the A 1 AR, mutation of Glu-16 in TM1 results in broad decreases in agonist affinity, and mutation of Ser-94 in TM3 results in a complete loss in ligand binding (7).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of the Adenine Binding Site of the Human A1 Adenosine Receptor

Rivkees¹,

Barbhaiya²,

IJzerman³

1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

To provide new insights into ligand-A 1 adenosine receptor (A 1 AR) interactions, site-directed mutagenesis was used to test the role of several residues in the first four transmembrane domains of the human A 1 AR. First, we replaced eight unique A 1 AR residues with amino acids present at corresponding transmembrane (TM) positions of A 2A ARs. We also tested the role of carboxamide amino acids in TMs 1-4, and the roles of Val-87, Leu-88, and Thr-91 in TM3. Following conversion of Gly-14 in TM1 to Thr-14, the affinity for adenosine agonists increased 100-fold, and after Pro-25 in TM1 was converted to Leu-25, the affinity for agonists fell. After conversion of TM3 sites Thr-91 to Ala-91, and Gln-92 to Ala-92, the affinity for N 6 -substituted agonists was reduced, and binding of ligands without N 6 substituents was eliminated. When Leu-88 was converted to Ala-88, the binding of ligands with N 6 substituents was reduced to a greater extent than ligands without N 6 substituents. Following conversion of Pro-86 to Phe-86, the affinity for N 6 -substituted agonists was lost, and the affinity for ligands without N 6 substitution was reduced. These observations strongly suggest that Thr-91 and Gln-92 in TM3 interact with the adenosine adenine moiety, and Leu-88 and Pro-86 play roles in conferring specificity for A 1 AR selective compounds. Using computer modeling based on the structure of rhodopsin, a revised model of adenosine-A 1 AR interactions is proposed with the N 6 -adenine position oriented toward the top of TM3 and the ribose group interacting with the bottom half of TMs 3 and 7.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Identification of the Adenine Binding Site of the Human A1 Adenosine Receptor

Rivkees¹,

Barbhaiya²,

IJzerman³

1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This classification was first proposed by Van Calker et al (1979), based on the relative potencies of adenosine and some of its derivatives as stimulants or inhibitors of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) formation in cultured brain cells. Although antagonists selective for adenosine A1-or A2-receptors have been described (Trevidi et al, 1990), to date pharmacological classification of these receptors has usually depended on the use of selective agonists.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of three adenosine receptor types

Gurden

Coates

Ellis

et al. 1993

British J Pharmacology

133

View full text Add to dashboard Cite

The purpose of the present study was to classify adenosine receptors into A1 and A2 subtypes in a wide range of isolated tissues and cell types (rat adipocytes and atria, guinea‐pig ileum and atria (A1); guinea‐pig aorta, dog coronary artery and human platelets and neutrophils (A2)) using the R‐ and S‐diastereoisomers of N‐phenylisopropyladenosine (PIA), N‐cyclopentyladenosine (CPA), the novel compound, N‐[(1S,trans)‐2‐hydroxycyclopentyl]adenosine (GR79236), N‐[(2‐methylphenyl)methyl]adenosine (metrifudil), 2‐(phenylamino)adenosine (CV1808), and 2‐[[2‐[4‐(2‐carboxyethyl)phenyl]ethyl]amino]‐N‐ethylcarboxamidoadenosine (CGS21680); N‐ethylcarboxamidoadenosine (NECA) was used as a standard. Results obtained in all tissue preparations previously reported to contain A1‐receptors could be described by a single rank order of agonist potency: CPA ≥ GR79236, R‐PIA ≥ NEC A > > S‐PIA ≥ metrifudil ≥ CV1808, CGS21680. In contrast, two distinct rank orders of agonist potency were observed in preparations previously reported to contain A2‐receptors. In dog coronary artery, human neutrophils and platelets the rank order of potency was: CV1808, CGS21680 ≥ NECA > R‐PIA ≥ metrifudil ≥ CPA > GR79236, S‐PIA. However, in guinea‐pig aorta the rank order was: NECA > metrifudil > R‐PIA, CPA > CV1808, GR79236 ≥ S‐PIA, CGS21680. The results of this study are consistent with the existence of three types of adenosine receptor: A1‐and two subtypes of A2‐receptor. The receptor present in dog coronary artery, human platelets and neutrophils, probably corresponds to the A2a subtype, whilst that present in the guinea‐pig aorta may be of the A2b subtype.

show abstract

New insights into the molecular mechanisms of A1 adenosine receptor action

1998

View full text Add to dashboard Cite

A1 adenosine receptors (A1ARs) mediate the effects of adenosine in many tissues, making this receptor subtype an extremely important transducer of adenosine action. Recent structure‐function and computer modeling studies based on the structure of mammalian rhodopsin suggest that the upper part of the purine ring and the N6‐substituent of adenosine interact with Thr91 and Gln92 in TM3, and the ribose moiety interacts with Thr277 and His278 in TM7, and Ser94 in TM3. When contemporary methods are applied to examine sites of A1AR expression in the brain, axons are now found to express A1ARs at very high levels, and functional studies show that adenosine can influence mammalian nerve conduction. A1ARs are expressed in the brain and heart at early embryonic stages, raising the intriguing possibility that adenosine exerts important effects during development, and adenosine may be one of the most potent regulators of embryonic cardiac function. These observations provide new insights into the sites and mechanisms of A1AR action. Drug Dev. Res. 45:93–102, 1998. © 1998 Wiley‐Liss, Inc.

show abstract

Structure-Activity Relationships of Adenosine A1 and A2 Receptors

Cited by 26 publications

References 63 publications

Identification of the Adenine Binding Site of the Human A1 Adenosine Receptor

Identification of the Adenine Binding Site of the Human A1 Adenosine Receptor

Functional characterization of three adenosine receptor types

New insights into the molecular mechanisms of A1 adenosine receptor action

Contact Info

Product

Resources

About