title: Ribose modified nucleosides and nucleotides as ligands for purine receptors.
abstract: Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3',5'-bisphosphate derivatives act as selective P2Y1 antagonists/partial agonists. The ribose moiety was replaced with carbocyclics, smaller and larger rings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built into the ribose rings of nucleoside and nucleotide ligands using the methanocarba approach, i.e. fused cyclopropane and cyclopentane rings in place of ribose, suggesting a preference for the Northern (N) conformation among ligands for P2Y1 and A1 and A3ARs.
authors.affiliation: Molecular Recognition Section, LBC, NIDDK, National Inst. of Health, Bethesda, Maryland 20902, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: R G
authors.initials: RG
authors.lastname: Ravi
authors.forename: E
authors.initials: E
authors.lastname: Nandanan
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Moro
authors.forename: Y C
authors.initials: YC
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Barak
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
authors.forename: X D
authors.initials: XD
authors.lastname: Ji
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009705:Nucleosides / Q000378:metabolism* / Q000494:pharmacology; D009711:Nucleotides / Q000378:metabolism* / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D012266:Ribose / Q000031:analogs & derivatives*
chemical_list: D008024:Ligands; D009705:Nucleosides; D009711:Nucleotides; C546382:P2RY1 protein, human; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D012266:Ribose