Chemistry Reference
In-Depth Information
Table 15.1 Summary of biological data for key backup compounds compared
to PHA-543613.
O
O
O
N
N
N
N
N
N
O
N
N
H
H
O
H
O
O
PHA-543613 (11)
PHA-568487 (18e)
PHA-709829 (21f)
PHA-543613
PHA-568487
PHA-709829
.
a7/5-HT
3
EC
50
(nM)
65
11
260
46
a7 nAChR K
i
(nM)
9.0
44
3.4
In vivo rat PK CL (mL/min/kg)
33
5
58
10
72
25
Half-life (min)
36
6
0.9
0.1
48
0
Vss (L/kg)/F(%)
1.8/74
2.1/18
2.4/40
In vivo RAG MED (mg/kg)/
plasma conc. (nM)
0.24/130
0.02/16
0.10/60
Acute Dog ECG QTc NOEL
(mM)/TI
5.7/9 fold
>16/>140
fold
>22/110 fold
Dog seizure C
max
(mM)/TI
>51/>240
fold
EC
50
, half maximal effective concentration; K
i
, binding anity; RAG MED: rat auditory gating
assay minimum ecacious dose; ECG, electrocardiography; QTc, Q wave, T wave cycle; NOEL, no
adverse effects levels; N.D., not determined.
2.6/17 fold
>120/>560
fold
160
PNU-282987
Nicotine
GTS-21
PHA-568487
140
120
100
80
60
40
20
0
0.1
1
10
100
1000
10000
Concentration (nM)
Figure 15.11
Desensitization concentration-response of PHA-568487 compared to
reference compounds.
a7 nAChRs in a concentration-dependent manner similar to that of other
known a7 nAChR agonists such as PNU-282987,
17
nicotine, and GTS-21
(Figure 15.11). In addition, at concentrations lower than those required to
activate the receptor, PHA-568487 positively modulated a7 nAChR function,
whereas other known a7 nAChR agonists lacked this modulatory effect
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