TABLE 1

Structures and modulation of binding and activity at the hDAT ([125I]RTI-55, unless noted) of (N)-methanocarba adenosine derivatives

The derivatives include simple C2 derivatives (compounds 1, 2 and 21), alkyne compounds 3–20 (5′-amides) and 22–24 (truncated), and triazole derivatives (compounds 25–32). Each compound that produced an effect is associated with data for inhibition or enhancement, in separate columns. —, no effect.Embedded Image
Compounds 1, 3–9 and 11–19, and 10
Embedded ImageCompounds 20, 2 and 21–24, and 25–32

Compound NumberaR1R2 or R3DAT Binding Inhibition,bKiDAT Binding Enhancement,b EC50Dopamine Uptake Assay IC50c
nMnM or % of controlnM
1Embedded ImageClaaND
2Embedded ImageCl>10,000 (4)>10,000 (3)
3Embedded ImageEmbedded ImageaaND
4Embedded ImageEmbedded Image>2500a (5)>10,000 (2)
5Embedded ImageEmbedded Image2650 ± 300d (6)>10,000 (2)
6CH3Embedded Image70 ± 26e (4), 690% ± 180%92 ± 16 (5)
7CH3Embedded Image540 ± 160e (5), 194% ± 12%>9500 (3)
8CH3Embedded Image446 ± 76 (8), 387% ± 48%3170 ± 380 (5)
9CH3Embedded Image35.1 ± 8.4e (5), 550% ± 110%253 ± 92 (5)
10N,N-di-CH3Embedded ImageaaND
11C2H5Embedded Image300 ± 150e (6), 760% ± 260%206 ± 61 (4)
12(CH2)2CH3Embedded Image1120 ± 220e (4), 268% ± 32%>8700 (4)
13Embedded ImageEmbedded Image560 ± 190e (6), 251% ± 30%>6600 (4)
14Embedded ImageEmbedded ImageaaND
15Embedded ImageEmbedded ImageaaND
16CH3Embedded Image9.1 ± 1.7e (4), 217% ± 24%229 ± 30 (3)
17CH3Embedded Image>10,000d (2)>10,000d (2)>10,000 (2)
18CH3Embedded ImageaaND
19CH3Embedded Image3370 ± 820e (3), 163% ± 14%>10,000 (2)
20CH3Embedded Image>10,000a (2)>10,000 (2)
21Embedded ImageHaaND
22Embedded ImageEmbedded Image3950 ± 900a (3)>10,000 (3)
23CH3Embedded Image4110 ± 540 (3), 277% ± 36%>10,000 (2)
24C2H5Embedded Image>7700 (9), 163.2% ± 8.6%>10,000 (2)
25CH3Embedded Image>10,000 (4)>10,000 (4)>10,000 (2)
26CH3Embedded Image>7100 (9), 136.2% ± 8.0%>10,000 (2)
27CH3Embedded Image(Ki 4.48 µM)dND
28CH3Embedded ImageaaND
29Embedded ImageEmbedded ImageaaND
30Embedded ImageEmbedded ImageaaND
31Embedded ImageEmbedded Image7300 ± 1700d (3)>10,000 (2)
32CH3Embedded Image>10,000 (2)>10,000 (2)
  • ND, not determined.

  • a Found to have negligible or no modulation of [3H]methyl (1R,2S,3S)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate binding at the hDAT by the PDSP (see Supplemental Material; Supplemental Table 1).

  • b Modulation of [125I]RTI-55 binding (inhibition, enhancement, or undetermined effect). Values are expressed as the mean ± S.E.M. of n values (in parentheses). For radioligand binding enhancement, a maximal % is given.

  • c Inhibition of DA uptake in HEK cells expressing the DAT. Values are expressed as the mean ± S.E.M. of n values (in parentheses). AR affinities are given for reported compounds in Supplemental Table 2 (see Supplemental Material).

  • d Found to inhibit [3H]methyl (1R,2S,3S)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate binding at the hDAT by the PDSP (see Supplemental Material; Supplemental Table 1).

  • e Found to enhance [3H]methyl (1R,2S,3S)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate binding at the hDAT by the PDSP (see Supplemental Material; Supplemental Table 1).