Synthesis and biological activity of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine: water-soluble and peripherally selective adenosine agonists.
A series of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine was synthesized, revealing that N6-(p-sulfophenyl)adenosine (10b) is a moderately potent (Ki vs [3H]PIA in rat cortical membranes was 74nM) and A1-selective (120-fold) adenosine agonist, of exceptional aqueous solubility of > 1.5 g/mL (approximately 3 M). Compound 10b was very potent in inhibiting synaptic potentials in gerbil hippocampal slices with an IC50 of 63 nM. At a dose of 0.1 mg/kg ip in rats, 10b inhibited lipolysis (a peripheral A1 effect) by 85% after 1 h. This in vivo effect was reversed using the peripherally selective A1-antagonist 1,3-dipropyl-8-[p-(carboxyethynyl)phenyl]xanthine (BW1433). The same dose of 10b in NIH Swiss mice (ip) was nearly inactive in locomotor depression, an effect that has been shown to be centrally mediated when elicited by lower doses of other potent adenosine agonists, such as N6-cyclohexyladenosine (CHA) (Nikodijevic et al. FEBS Lett. 1990, 261, 67). HPLC studies of biodistribution of a closely related and less potent homologue, N6-[4-(p-sulfophenyl)butyl]adenosine indicated that a 25 mg/kg ip dose in mice resulted in a plasma concentration after 30 min of 0.46 micrograms/mL and no detectable drug in the brain (detection limit < 0.1% of plasma level). Although 10b at doses > 0.1 mg/kg in mice depressed locomotor activity, this depression was unlike the effects of CHA and was reversible by BW1433. These data suggest that 10b is a potent adenosine agonist in vivo and shows poor CNS penetration.
Jacobson
K A
KA
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Nikodijevic
O
O
Ji
X D
XD
Berkich
D A
DA
Eveleth
D
D
Dean
R L
RL
Hiramatsu
K
K
Kassell
N F
NF
van Galen
P J
PJ
Lee
K S
KS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects; D005849:Gerbillinae; D066298:In Vitro Techniques; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011983:Receptors, Purinergic / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D011983:Receptors, Purinergic; D013451:Sulfonic Acids; D000241:Adenosine