Table 1.
In vitro pharmacological data for UDPG 1, UDP 3, and their analogues (nonsugar β-phosphoesters and other derivatives of UDP) in the inhibition of cAMP formation at recombinant hP2Y14 receptors expressed in HEK-293 cells stably transfected with the hP2Y14 and in the stimulation of PLC at recombinant hP2Y6 receptors stably expressed in 1321N1 cells. Unless noted: X, Y = O, Z = H.
 | ||||
|---|---|---|---|---|
| Compound | Modification | Structure R = | EC50, nMa | |
| UDP-sugars | hP2Y14 | hP2Y6 | ||
| 1 | UDP-[1]glucose |  |
400±90 | 16,000 |
| 2b | 2-thio-UDP-[1]glucose, |  |
11±5 | >10,000c |
| UDP analogues | hP2Y14 | hP2Y6 | ||
| 3 | UDP | HO | 160±40 | 530±60 |
| 4 | 2-thio-UDP | HO, X1 = S | 1.92±0.69 | 447±100 |
| 5 | 4-thio-UDP | HO, X2 = S | 320±130 | 2360±710 |
| 6 | Up2-β-Me-phosphonate | R = CH3 | 4580±1560 | 8000±1630 |
| 7 | N4-OCH3-CDP | HO, X2 = N-OCH3 | 3320±1620 | 70±7b |
| 8d | (N)-methanocarba UDP (pure enantiomer) | HO | NE | NE |
| 9d | (S)-methanocarba UDP (pure enantiomer) | HO | NE | 42±8b |
| 10 | Up-CH2-p (α,β-methylene UDP) | HO, Y = CH2 | 11±6 | 339±97 |
| 11 | 2-thio-Up-CH2-p (α,β-methylene-2-thio-UDP) | HO, Y = CH2, X1 = S | 0.92±0.09 | 1990±370 |
| 12b,e | Up-CF2-p (α,β-difluoromethylene UDP) | HO, Y = CF2 | 63±9 | NEb |
| 13 | 5-I-Up-CF2-p | HO, Y = CF2, Z = I | 142±74 | 127±24 |
| UDP β-esters | hP2Y14 | hP2Y6 | ||
| 14 | Up2-OMe | CH3O | 2730±680 | >10,000c |
| 15 | 2-thio-Up2-OMe | CH3O, X1 = S | 56±19 | >10,000c |
| 16 | 4-thio-Up2-OMe | CH3O, X2 = S | NE | 10,400±4200 |
| 17 | 2-thio-Up2-OEt | CH3CH2O, X1 = S | 39±20 | >10,000c |
| 18e | 2-thio-Up2-OPr | CH3(CH2)2O, X1 = S | 40±6 | 9100±1430 |
| 19 | Up2-O(CH2)2CN | O(CH2)2CN | 7460±2340 | >10,000c |
| 20 | Up2-O(CH2)2C≡CH | O(CH2)2C≡CH | 480±161 | 1520±100 |
| 21 | 2-thio-Up2-O(CH2)2C≡CH | O(CH2)2C≡CH, X1 = S | 11.0±1.4 | >10,000c |
| 22 | Up2-OCH2CHOHCH2OH | OCH2CH(OH)-CH2OH | 1600±600 | >10,000c |
| 23 | Up2-OCH(CH2OH)2 | OCH(CH2OH)2 | 167±32 | >10,000c |
| 24 | Up2-OC(CH3)3 | OC(CH3)3 | 252±93 | 10,800±1900 |
| 25 | 2-thio-Up2-OC(CH3)3 | OC(CH3)3, X1 = S | 32±1 | 2040±600 |
| 26 | Up2-O -cyclohexyl |  |
5160±1830 | >10,000c |
| 27 | Up2-OC6H5 |  |
768±304 | 7400±860 |
| 28 | Up2-OC6H4-4-NO2 |  |
1490±490 | 2760±810 |
| 29 | Up2-OC6H4-3-Cl |  |
1800±860 | 7370±530 |
| 30 | Up2-OC6H4-4-OCH3 |  |
1900±490 | >10,000c |
Agonist potencies reflect stimulation of phospholipase C, unless noted, and were calculated using a four-parameter logistic equation and the GraphPad software package (GraphPad, San Diego, CA). EC50 values (mean ± standard error) represent the concentration at which 50% of the maximal effect is achieved. Relative efficacies (%) were determined by comparison with the effect produced by a maximal effective concentration of reference agonist (UDP-glucose, 1) in the same experiment. If no maximal effect is given, then 100% efficacy was achieved. N = 3.
Potency at P2Y6 receptor reported in Maruoka et al.,15 Besada et al.,17 and Ko et al.18 Potency at P2Y14 receptor reported in Ko et al.12,13
<50% effect at 10 μM.
Structure is given below.
12, MRS2802; 18, MRS2907.14
NE - no effect at 10 μM. 