Synthesis and biological activity of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine: water-soluble and peripherally selective adenosine agonists

Abstract

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.

Figure 1

Synthesis of sulfoaralkylamine and sulfoalkylamine intermediates.

Figure 2

Synthesis of N⁶-(sulfoaralkyl)- and N⁶-(sulfoalkyl)-adenosine analogs.

Figure 3

Time course for the effects of sulfoadenosine derivatives on lipolytic activity in rats (n = 3 for each point). Serum glycerol levels were measured enzymatically. Key: animals injected with 10b at 0.1 mg/kg sc (open symbols) or 12b at 1.0 mg/kg (closed symbols) for adenosine agonist alone (squares) or combination of agonist and BW1433, 4.0 mg/kg sc (triangles). BW1433 alone raised serum glycerol levels by a small amount, from 296 ± 20 μM before injection to 326 ± 15 μM at 60 min postinjection.

Figure 4

(A) Effects of N⁶-(4-sulfophenyl)adenosine, 10b, on locomotor activity in mice. Key: vehicle-injected animals (open squares), 10b at 0.3 mg/kg ip (closed squares), 10b at 1.0 mg/kg ip (circles); n = 7–25. P values for control vs 0.3 mg/kg 10b were <0.01 at 10 min and <0.001 at 20 min. (B) Reversal by the adenosine antagonist BW1433 of the locomotor depression elicited by a 0.3 mg/kg dose of compound 10b. Key: vehicle-injected animals (open squares), 10b at 0.3 mg/kg ip (closed squares), 10b + BW1433, 4.0 mg/kg ip (triangles), BW1433 alone (circles); n = 10–25.

Figure 5

Effects of compound 11b on body temperature in rats: (a) by ip administration at the dose indicated or (b) by icv administration in a cannulated animal.