639010-94-9Relevant articles and documents
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 (1999)
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.
Optically Active Mexiletine Analogues as Stereoselective Blockers of Voltage-Gated Na+ Channels
Franchini, Carlo,Carocci, Alessia,Catalano, Alessia,Cavalluzzi, Maria M.,Corbo, Filomena,Lentini, Giovanni,Scilimati, Antonio,Tortorella, Paolo,Camerino, Diana Conte,De Luca, Annamaria
, p. 5238 - 5248 (2007/10/03)
Optically active mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenyle-thanamine [(R)-3b], was 27-fold more potent than (R)-mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.
