N-substituted adenosines as novel neuroprotective A(1) agonists with diminished hypotensive effects

The synthesis and pharmacological profile of a series of neuroprotective ad enosine agonists are described. Novel Al agonists with potent central nervo us 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 t erms of their in vitro profiles, both binding and functional, and in vivo a ctivity in relevant animal models. Neuroprotective properties assessed afte r postischemic dosing in a Mongolian gerbil severe temporary forebrain isch emia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an Al functional assay show similarities to some referenc e adenosine agonists. However, the new compounds we describe exhibit dimini shed cardiovascular effects in both anesthetized and awake rats when compar ed to reference Al agonists such as (R)phenylisopropyladenosine (R-PIA, 5), N-cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2-hydroxycyclopentyl]ade nosine (GR 79236, 26), N-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl] adenosine (Metrifudil, 28). In mouse perman ent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-be nzothiazoly)]thiol -2-propyl]adenosine (NNC 21-0136, 12) exhibited signific ant 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-beta-carb oline-3-carboxylate-induced seizures, and in mouse locomotor activity highe r doses are required to reach ED50 values than for reference AL agonists. W e conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1-eridinyl]adeno sine (NNC 21-0147 , 13), representatives of a new series of P-1 ligands, reinforce the fact t hat novel selective adenosine Al agonists have potential in the treatment o f cerebral ischemia in humans.