Ligand |
|
|
|
|
|
|
|
|
|
|
|
[3H]nemonapride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
10.9
|
pKd
|
75
|
|
⤷ |
pKd
10.9
[75]
|
[3H]spiperone
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
10.2
|
pKd
|
23,51,139
|
|
⤷ |
pKd
10.2
(Kd 5.7x10-11 M)
[23,51,139]
|
[3H]raclopride
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
8.9
|
pKd
|
65
|
|
⤷ |
pKd
8.9
(Kd 1.2x10-9 M)
[65]
|
[3H]N-methylspiperone
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
10.7
|
pKi
|
102
|
|
⤷ |
pKi
10.7
[102]
|
benperidol
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
10.6
|
pKi
|
109
|
|
⤷ |
pKi
10.6
(Ki 2.7x10-11 M)
[109]
|
blonanserin
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
9.9
|
pKi
|
88
|
|
⤷ |
pKi
9.9
(Ki 1.4x10-10 M)
[88]
|
pipotiazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
9.7
|
pKi
|
117
|
|
⤷ |
pKi
9.7
(Ki 2x10-10 M)
[117]
|
risperidone
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
9.4
|
pKi
|
10
|
|
⤷ |
pKi
9.4
(Ki 4.4x10-10 M)
[10]
|
perphenazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.9 – 9.6
|
pKi
|
62,106
|
|
⤷ |
pKi
8.9 – 9.6
(Ki 1.4x10-9 – 2.6x10-10 M)
[62,106]
|
perospirone
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
9.2
|
pKi
|
107
|
|
⤷ |
pKi
9.2
(Ki 6x10-10 M)
[107]
|
eticlopride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
9.2
|
pKi
|
73,123
|
|
⤷ |
pKi
9.2
[73,123]
|
trifluoperazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.9 – 9.0
|
pKi
|
62,108
|
|
⤷ |
pKi
8.9 – 9.0
(Ki 1.3x10-9 – 9.6x10-10 M)
[62,108]
|
asenapine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.9
|
pKi
|
112
|
|
⤷ |
pKi
8.9
(Ki 1.2x10-9 M)
[112]
|
terguride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.9
|
pKi
|
84
|
|
⤷ |
pKi
8.9
[84]
|
spiperone
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
8.4 – 9.4
|
pKi
|
73,85,118,123
|
|
⤷ |
pKi
8.4 – 9.4
[73,85,118,123]
|
fluphenazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.8
|
pKi
|
99
|
|
⤷ |
pKi
8.8
(Ki 1.44x10-9 M)
[99]
|
flupentixol
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.8
|
pKi
|
40
|
|
⤷ |
pKi
8.8
(Ki 1.5x10-9 M)
[40]
|
nafadotride
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
8.8
|
pKi
|
102
|
|
⤷ |
pKi
8.8
[102]
|
lurasidone
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
8.8
|
pKi
|
54
|
|
⤷ |
pKi
8.8
(Ki 1.68x10-9 M)
[54]
|
olanzapine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.7
|
pKi
|
10
|
|
⤷ |
pKi
8.7
(Ki 2.1x10-9 M)
[10]
|
mesoridazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.7
|
pKi
|
31
|
|
⤷ |
pKi
8.7
(Ki 2.2x10-9 M)
[31]
|
roxindole
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.6
|
pKi
|
84
|
|
⤷ |
pKi
8.6
[84]
|
ziprasidone
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.6
|
pKi
|
10
|
|
⤷ |
pKi
8.6
(Ki 2.8x10-9 M)
[10]
|
chlorprothixene
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.5
|
pKi
|
128
|
|
⤷ |
pKi
8.5
(Ki 2.96x10-9 M)
[128]
|
nafadotride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.5
|
pKi
|
101
|
|
⤷ |
pKi
8.5
[101]
|
raclopride
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
7.7 – 9.3
|
pKi
|
102,118
|
|
⤷ |
pKi
7.7 – 9.3
[102,118]
|
domperidone
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
8.5
|
pKi
|
118
|
|
⤷ |
pKi
8.5
[118]
|
sertindole
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.0 – 8.9
|
pKi
|
61-62,106
|
|
⤷ |
pKi
8.0 – 8.9
(Ki 9.1x10-9 – 1.2x10-9 M)
[61-62,106]
|
prochlorperazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.4
|
pKi
|
12
|
|
⤷ |
pKi
8.4
(Ki 3.61x10-9 M)
[12]
|
haloperidol
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
8.3
|
pKi
|
118
|
|
⤷ |
pKi
8.3
[118]
|
(+)-sulpiride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.2
|
pKi
|
40
|
|
⤷ |
pKi
8.2
(Ki 6x10-9 M)
[40]
|
L-741,626
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.9 – 8.5
|
pKi
|
46,64
|
|
⤷ |
pKi
7.9 – 8.5
[46,64]
|
domperidone
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.9 – 8.4
|
pKi
|
40,116
|
|
⤷ |
pKi
7.9 – 8.4
(Ki 1.26x10-8 – 3.98x10-9 M)
[40,116]
|
loxapine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.9 – 8.3
|
pKi
|
62,108
|
|
⤷ |
pKi
7.9 – 8.3
(Ki 1.2x10-8 – 5x10-9 M)
[62,108]
|
(+)-butaclamol
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.5 – 8.7
|
pKi
|
24,40,73,123
|
|
⤷ |
pKi
7.5 – 8.7
[24,40,73,123]
|
haloperidol
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.4 – 8.8
|
pKi
|
40,73,83,116,124
|
|
⤷ |
pKi
7.4 – 8.8
[40,73,83,116,124]
|
raclopride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.0
|
pKi
|
85
|
|
⤷ |
pKi
8.0
(Ki 1x10-8 M)
[85]
|
zotepine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
8.0
|
pKi
|
105
|
|
⤷ |
pKi
8.0
(Ki 1.1x10-8 M)
[105]
|
(-)-stepholidine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.9
|
pKi
|
82
|
|
⤷ |
pKi
7.9
(Ki 1.16x10-8 M)
[82]
|
pimozide
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.0 – 8.8
|
pKi
|
40,116
|
|
⤷ |
pKi
7.0 – 8.8
[40,116]
|
amisulpride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.8 – 8.0
|
pKi
|
77,116,118
|
|
⤷ |
pKi
7.9 – 8.0
[77,116]
pKi
7.8
[118]
|
pimozide
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
7.6
|
pKi
|
118
|
|
⤷ |
pKi
7.6
[118]
|
sulpiride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.2 – 7.9
|
pKi
|
24
|
|
⤷ |
pKi
7.2 – 7.9
(Ki 6x10-8 – 1.2x10-8 M)
[24]
|
metoclopramide
|
|
|
|
|
|
|
|
|
|
|
Mm |
Antagonist |
7.5
|
pKi
|
79
|
|
⤷ |
pKi
7.5
(Ki 2.88x10-8 M)
[79]
|
chlorpromazine
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
7.5
|
pKi
|
118
|
|
⤷ |
pKi
7.5
[118]
|
lumateperone
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.5
|
pKi
|
71,115
|
|
⤷ |
pKi
7.5
(Ki 3.2x10-8 M)
[71,115]
|
chlorpromazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.0 – 7.6
|
pKi
|
40,116
|
|
⤷ |
pKi
7.0 – 7.6
[40,116]
|
quetiapine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.2
|
pKi
|
10
|
|
⤷ |
pKi
7.2
(Ki 6.9x10-8 M)
[10]
|
(-)-sulpiride
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
6.3 – 8.0
|
pKi
|
40,116,123
|
|
⤷ |
pKi
6.3 – 8.0
(Ki 5.2x10-7 – 1x10-8 M)
[40,116,123]
|
R-VK4-40
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.1
|
pKi
|
56
|
|
⤷ |
pKi
7.1
(Ki 7.58x10-8 M)
[56]
|
(+)-sulpiride
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
7.0
|
pKi
|
118
|
|
⤷ |
pKi
7.0
[118]
|
ML321
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
7.0
|
pKi
|
133-134
|
|
⤷ |
pKi
7.0
(Ki 1x10-7 M)
[133-134]
|
trans-flupenthixol
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
6.9
|
pKi
|
40
|
|
⤷ |
pKi
6.9
(Ki 1.2x10-7 M)
[40]
|
EGIS-11150
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
6.9
|
pKi
|
41
|
|
⤷ |
pKi
6.9
(Ki 1.2x10-7 M)
[41]
|
(+)-UH232
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
6.4 – 7.1
|
pKi
|
40,118
|
|
⤷ |
pKi
6.4 – 7.1
[40,118]
|
promazine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
6.5
|
pKi
|
25
|
|
⤷ |
pKi
6.5
(Ki 3x10-7 M)
[25]
|
(+)-UH232
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
6.4
|
pKi
|
118
|
|
⤷ |
pKi
6.4
[118]
|
clozapine
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
5.8 – 6.9
|
pKi
|
40,73,112,116,123
|
|
⤷ |
pKi
5.8 – 6.9
[40,73,112,116,123]
|
clozapine
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
6.2
|
pKi
|
118
|
|
⤷ |
pKi
6.2
[118]
|
(+)-S-14297
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
5.5
|
pKi
|
85
|
|
⤷ |
pKi
5.5
[85]
|
(+)-SCH-23390
|
|
|
|
|
|
|
|
|
|
|
Hs |
Antagonist |
5.3
|
pKi
|
40
|
|
⤷ |
pKi
5.3
[40]
|
iloperidone
|
|
|
|
|
|
|
|
|
|
|
Rn |
Antagonist |
7.0
|
pIC50
|
121
|
|
⤷ |
pIC50
7.0
(IC50 1.1x10-7 M)
[121]
Description: Measuring displacement of [3H]spiperone from rat striatum.
|
metopimazine
|
|
|
|
|
|
|
|
|
|
|
N/A |
Antagonist |
-
|
-
|
|
|
⤷ |
|
alizapride
|
|
|
|
|
|
|
|
|
|
|
N/A |
Antagonist |
-
|
-
|
|
|
⤷ |
|
|
Terguride/roxindole have been reported to act as partial agonists at the D2S receptor and as antagonists at the D2L receptor. Perphenazine is an antagonist at both the D2S and D2L receptors [122]. The approved drug mesoridazine, although consisting of 4 stereoisomers, appears to be selective for the D2 receptor [31], especially when examining the data for the two highest affinity isomers, compounds 2 and 5. Across the 3 dopamine receptors, compounds 2 and 5 have the same order of potency (D2>D3>D1). The data shown in the table above is for compound 2. Mesoridazine is also a selective antagonist of the serotonin 5-HT2A receptor. Zotepine has a Ki of 5.4nM for the D2S receptor isoform [105]. The β-arrestin biased ligands UNC9975, UNC0006 and UNC9994, do not activate D2 receptor-mediated Gi-regulated inhibition of cAMP production, but rather are functionally-selective antagonists of the interaction between D2 receptor and β-arrestin-2 [3]. |