124555-18-6Relevant articles and documents
Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity
Knight, Anthony,Hemmings, Jennifer L.,Winfield, Ian,Leuenberger, Michele,Frattini, Eugenia,Frenguelli, Bruno G.,Dowell, Simon J.,Lochner, Martin,Ladds, Graham
, p. 947 - 964 (2016/02/23)
A series of N6-bicyclic and N6-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N6-adamantyl substitution in combination with 5′-N-ethylcarboxamido or 5′-hydroxymethyl groups. In addition, we determined that 5′-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.
Partial and full agonists of A1 adenosine receptors
-
Page 13, (2010/02/05)
Disclosed are novel compounds that are partial and full A1 adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, myocardial infarction and hyperlipidemia.
N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects
Knutsen, Lars J. S.,Lau, Jesper,Petersen, Hans,Thomsen, Christian,Weis, Jan U.,Shalmi, Michael,Judge, Martin E.,Hansen, Anker Jon,Sheardown, Malcolm J.
, p. 3463 - 3477 (2007/10/03)
The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A1 agonists with potent central nervous system effects and diminished influence on the cardiovascular system are reported and compared to selected reference adenosine-agonists. The novel compounds featured are derived structurally from two key lead structures: 2- chloro-N-(1-phenoxy-2-propyl)adenosine (NNC 21-0041, 9) and 2-chloro-N-(1- piperidinyl)adenosine (NNC 90-1515, 4). The agonists are characterized in terms of their in vitro profiles, both binding and functional, and in vivo activity in relevant animal models. Neuroprotective properties assessed after postischemic dosing in a Mongolian gerbil severe temporary forebrain ischemia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an A1 functional assay show similarities to some reference adenosine agonists. However, the new compounds we describe exhibit diminished cardiovascular effects in both anesthetized and awake rats when compared to reference A1 agonists such as (R)phenylisopropyladenosine (R-PIA, 5), N- cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2- hydroxycyclopentyl]adenosine (GR 79236, 26), N-cyclohexyl-2'-O- methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl]adenosine (Metrifudil, 28). In mouse permanent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine (NNC 21-0136, 12) exhibited significant neuroprotection at the remarkably low total intraperitoneal dose of 0.1 mg/kg, a dose at which no cardiovascular effects are observed in conscious rats. The novel agonists described inhibit 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED50 values than for reference A1 agonists. We conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1- piperidinyl]adenosine (NNC 21-0147, 13), representatives of a new series of P1 ligands, reinforce the fact that novel selective adenosine A1 agonists have potential in the treatment of cerebral ischemia in humans.
Purine derivatives
-
, (2008/06/13)
A compound of formula (I), or a pharmaceutically acceptable salt thereof: STR1 wherein X is hydrogen, amino, halogen, hydroxy, lower alkoxy or lower alkyl andR 1 is STR2 wherein Y is methylene or a valence bond, R 2 and R 5 is H or lower, straight or branched alkyl,R 3 is H or lower alkyl, orR 2 and R 3 can together form a cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring,Z is oxygen, methylene, sulphur, sulphonyl or a valence bond,R 4 is H, lower alkyl, aralkyl, a mono or bicyclic aromatic system optionally substituted with various groups.The compounds have been found useful for treating central nervous system ailments.
2,N-6-disubstituted adenosines and their antihypertensive methods of use
-
, (2008/06/13)
Compounds of formula (I) STR1 wherein X represents a hydrogen or chlorine atom, or a methyl group; and R represents a cycloalkyl or cycloalkenyl ring containing 5 to 8 carbon atoms, which ring is substituted by a hydroxy group, and is optionally substitut
