title: The importance of alkynyl chain presence for the activity of adenine nucleosides/nucleotides on purinergic receptors.
abstract: The first demonstrations in the early seventies that adenosine had marked effects in the cerebral cortex, which were independent of its role in intermediary metabolism and could be antagonised by methylxanthines, were followed by the observations that other purine derivatives, notably ATP, may also play a critical role in cell function. In 1978 Burnstock first introduced the terms Pl for the nucleoside receptors and P2 for the nucleotide receptors, based on the most fundamental divisions of purine receptors between those for nucleosides such as adenosine and those for nucleotides such as ATP. At present, the P1 (adenosine) receptor family presents 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors and P2Y metabotropic G protein-coupled receptors (GPCRs). While knowledge on the purinergic receptor pharmacology was increasing, the development of potent and selective ligands for these receptors has been a target of medicinal chemistry research for several decades. In particular, synthesis of 2-substituted adenosines was carried out in many laboratories starting from seventies aimed at finding adenosine derivatives more resistant than the parent nucleoside to rapid uptake into cells, to deamination by adenosine deaminase, and to phosphorylation by adenosine kinase. In the present review the synthesis of alkynyl derivatives of adenine, adenosine, N-alkylcarboxamidoadenosine, and adenine nucleotides, which have been tested on purinergic receptors, will be summarized. Furthermore, the contribution of chemistry, molecular modelling, and pharmacology to the development of structure-activity relationships in this class of purinergic receptor ligands will be outlined.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Dal Ben
authors.forename: M
authors.initials: M
authors.lastname: Buccioni
authors.forename: C
authors.initials: C
authors.lastname: Lambertucci
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: R
authors.initials: R
authors.lastname: Volpini
authors.forename: G
authors.initials: G
authors.lastname: Cristalli
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000227:Adenine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D006801:Humans; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism*; D011684:Purine Nucleosides / Q000737:chemistry* / Q000378:metabolism; D011983:Receptors, Purinergic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000227:Adenine Nucleotides; D009711:Nucleotides; D011684:Purine Nucleosides; D011983:Receptors, Purinergic; D000225:Adenine