ArticleJournal of medicinal chemistry2001
Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A(3) receptor with selectively enhanced affinity for amine-modified nucleosides.
Article in Journal of medicinal chemistry, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 82 citations in OpenAlex.
- E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling.Accounts of chemical research · 2025Article
- Neurotransmitters, Cell Types, and Circuit Mechanisms of Motor Skill Learning and Clinical Applications.Frontiers in neurology · 2021Review
- Structural Probing and Molecular Modeling of the A₃ Adenosine Receptor: A Focus on Agonist Binding.Molecules (Basel, Switzerland) · 2017Review
- Probing GPCR structure: adenosine and P2Y nucleotide receptors.Methods in enzymology · 2013Article
- Ligand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A(1), A (2A), A (2B), and A (3) receptor antagonists.Journal of computer-aided molecular design · 2012Article
- Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.Journal of medicinal chemistry · 2012Article
- Remote control of neuronal signaling.Pharmacological reviews · 2011Review
- Engineering a GPCR-ligand pair that simulates the activation of D(2L) by Dopamine.ACS chemical neuroscience · 2010Article
- Evaluation of homology modeling of G-protein-coupled receptors in light of the A(2A) adenosine receptor crystallographic structure.Journal of medicinal chemistry · 2009Article
- Medicinal chemistry of the A3 adenosine receptor: agonists, antagonists, and receptor engineering.Handbook of experimental pharmacology · 2009Review
- Marking embryonic stem cells with a 2A self-cleaving peptide: a NKX2-5 emerald GFP BAC reporter.PloS one · 2008Article
- On the applicability of GPCR homology models to computer-aided drug discovery: a comparison between in silico and crystal structures of the beta2-adrenergic receptor.Journal of medicinal chemistry · 2008Article
- Probing the binding site of the A1 adenosine receptor reengineered for orthogonal recognition by tailored nucleosides.Biochemistry · 2007Article
- Neoceptors: reengineering GPCRs to recognize tailored ligands.Trends in pharmacological sciences · 2007Review
- Synthesis of N6-substituted 3'-ureidoadenosine derivatives as highly potent agonists at the mutant A3 adenosine receptor.Nucleosides, nucleotides & nucleic acids · 2007Article
- Molecular modelling study of 2-phenylethynyladenosine (PEAdo) derivatives as highly selective A₃ adenosine receptor ligands.Purinergic signalling · 2006Article
- Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists.Journal of medicinal chemistry · 2006Article
- Invited Lectures : Overviews Purinergic signalling: past, present and future.Purinergic signalling · 2006Article
- Adenosine receptors as therapeutic targets.Nature reviews. Drug discovery · 2006Review
- Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors.Nucleosides, nucleotides & nucleic acids · 2006Review
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Adenosine A(3) receptors are of interest in the treatment of cardiac ischemia, inflammation, and neurodegenerative diseases. In an effort to create a unique receptor mutant that would be activated by tailor-made synthetic ligands, we mutated the human A(3) receptor at the site of a critical His residue in TM7, previously proposed to be involved in ligand recognition through interaction with the ribose moiety. The H272E mutant receptor displayed reduced affinity for most of the uncharged A(3) receptor agonists and antagonists examined. For example, the nonselective agonist 1a was 19-fold less potent at the mutant receptor than at the wild-type receptor. The introduction of an amino group on the ribose moiety of adenosine resulted in either equipotency or enhanced binding affinity at the H272E mutant relative to wild-type A(3) receptors, depending on the position of the amino group. 3'-Amino-3'-deoxyadenosine proved to be 7-fold more potent at the H272E mutant receptor than at the wild-type receptor, while the corresponding 2'- and 5'-amino analogues did not display significantly enhanced affinities. An 3'-amino-N(6)-iodobenzyl analogue showed only a small enhancement at the mutant (K(i) = 320 nM) vs wild-type receptors. The 3'-amino group was intended for a direct electrostatic interaction with the negatively charged ribose-binding region of the mutant receptor, yet molecular modeling did not support this notion. This design approach is an example of engineering the structure of mutant receptors to recognize synthetic ligands for which they are selectively matched on the basis of molecular complementarity between the mutant receptor and the ligand. We have termed such engineered receptors "neoceptors", since the ligand recognition profile of such mutant receptors need not correspond to the profile of the parent, native receptor.
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