N-substituted adenosines as novel neuroprotective A(1) agonists with diminished hypotensive effects.
The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A(1) 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 A(1) 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 A(1) 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-beta-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED(50) values than for reference A(1) 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 P(1) ligands, reinforce the fact that novel selective adenosine A(1) agonists have potential in the treatment of cerebral ischemia in humans.
Knutsen
L J
LJ
Health Care Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. L.Knutsen@Cerebrus.ltd.dk
Lau
J
J
Petersen
H
H
Thomsen
C
C
Weis
J U
JU
Shalmi
M
M
Judge
M E
ME
Hansen
A J
AJ
Sheardown
M J
MJ
D000241:Adenosine / Q000031:analogs & derivatives*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy; D002319:Cardiovascular System / Q000187:drug effects; D002460:Cell Line; D005849:Gerbillinae; D006168:Guinea Pigs; D007022:Hypotension / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D011919:Rats, Inbred Strains
D018696:Neuroprotective Agents; D058906:Purinergic P1 Receptor Agonists; D000241:Adenosine