JZ-IV-10 is a piperidine derivative related to nocaine which is a highly potent triple reuptake inhibitor (SNDRI).[1] The eugeroic modafinil, was used as a lead to fuel these compounds' discovery (J. Zhou, et al. 2004).[2] Although it turns out that the QSAR of the pharmacophoric elements do not appear to be strongly similar. The other isomers were also prepared, although they are weaker than the R,S probes invented in the current study (R. He, et al. 2005).[3]
JZ # |
R |
X |
Y |
[3H]NE |
[3H]DA |
[3H]5HT |
III-82 → ? |
Me |
-CO2H |
70.2 → ? |
121.2 → ? |
269.9 → ? |
III-48 → III-59 |
Ester |
OMe |
25 → 53 |
80 → 231 |
208 → 809 |
IV-22 → ? |
H |
10 → 31.1 |
114 → 107.8 |
170 → 774.9 |
IV-25 → IV-37 |
Me |
Amide |
NH2 |
39 → 178 |
159 → 209 |
557 → 5790 |
|
H |
10 → 31.1 |
114 → 107.8 |
170 → 774.9 |
III-62 → III-85 |
Me |
HNOH |
15 → 12 |
85 → 55 |
227 → 1795 |
IV-5 → IV-14 |
HNMe |
25 → 86 |
13 → 164 |
110 → 2033 |
IV-23 → IV-27 |
-NMe2 |
27 → 1249 |
116 → 2884 |
88 → 924 |
IV-10 → IV-15 |
NHPri |
0.8 → 20 |
1.0 → 248 |
1.1 → 473 |
IV-7 → IV-16 |
-N(CH2)5 |
0.68 → 460 |
83 → 379 |
4.5 → 825 |
III-84 → IV-34 |
H2 |
OH |
0.94 → 42 |
16 → 12 |
158 → 2183 |
IV-35 → IV-36 |
OMe |
6 → 25 |
50 → 15 |
191 → 469 |
III-86 → III-91 |
OAc |
3.6 → 29 |
35 → 9 |
57 → 87 |
III-87 → III-90 |
OBz |
4.5 → 18 |
68 → 32 |
6.7 → 199 |
IV-17 → IV-21 |
Het |
31.5 → 217.6 |
125.7 → 1,653 |
220.9 → 1,079 |
![JZ-IV-17 structure.png](//web.archive.org./web/20130426063703im_/http://upload.wikimedia.org/wikipedia/commons/thumb/2/2c/JZ-IV-17_structure.png/100px-JZ-IV-17_structure.png)
Upon treatment of the ligands with (H2O2 + AcOH) the sulfur atom is oxidized. The resultant molecules then lose most of their potency. This is not a major concern though (c.f. cimetidine, ranitidine). Little has been reported about the SAR of modafinil itself, and it is interesting to consider how these new findings could be applied retrospectively. The NRI selective molecules were employed as brain imaging agents to unravel details about the NE transporter.[4] NRIs are important probes, but they do not function as robust reinforcers.[5]
[edit] References
- ^ WO 2005041875
- ^ Zhou, J. .; He, R. .; Johnson, K. .; Ye, Y. .; Kozikowski, A. . (2004). "Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization". Journal of Medical Chemistry 47 (24): 5821–5824. doi:10.1021/jm040117o. PMC 1395211. PMID 15537337. edit
- ^ He, R.; Kurome, T.; Giberson, K.; Johnson, K.; Kozikowski, A. (2005). "Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors". Journal of Medicinal Chemistry 48 (25): 7970–7979. doi:10.1021/jm050694s. PMID 16335921. edit
- ^ Musachio, J.; Hong, J.; Ichise, M.; Seneca, N.; Brown, A.; Liow, J.; Halldin, C.; Innis, R. et al. (2006). "Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors". Bioorganic & Medicinal Chemistry Letters 16 (12): 3101–3104. doi:10.1016/j.bmcl.2006.03.066. PMID 16621532. edit
- ^ Wee, S. .; Wang, Z. .; He, R. .; Zhou, J. .; Kozikowski, A. .; Woolverton, W. . (2006). "Role of the increased noradrenergic neurotransmission in drug self-administration". Drug and alcohol dependence 82 (2): 151–157. doi:10.1016/j.drugalcdep.2005.09.002. PMID 16213110. edit
|
|
|
|
|
- Adamantanes: Amantadine
- Memantine
- Rimantadine; Aminotetralins: 7-OH-DPAT
- 8-OH-PBZI
- Rotigotine
- UH-232; Benzazepines: 6-Br-APB
- Fenoldopam
- SKF-38,393
- SKF-77,434
- SKF-81,297
- SKF-82,958
- SKF-83,959; Ergolines: Bromocriptine
- Cabergoline
- Dihydroergocryptine
- Epicriptine
- Lisuride
- LSD
- Pergolide; Dihydrexidine derivatives: 2-OH-NPA
- A-86,929
- Ciladopa
- Dihydrexidine
- Dinapsoline
- Dinoxyline
- Doxanthrine; Others: A-68,930
- A-77636
- A-412,997
- ABT-670
- ABT-724
- Aplindore
- Apomorphine
- Aripiprazole
- Bifeprunox
- BP-897
- CY-208,243
- Dizocilpine
- Etilevodopa
- Flibanserin
- Ketamine
- Melevodopa
- Modafinil
- Pardoprunox
- Phencyclidine
- PD-128,907
- PD-168,077
- PF-219,061
- Piribedil
- Pramipexole
- Propylnorapomorphine
- Pukateine
- Quinagolide
- Quinelorane
- Quinpirole
- RDS-127
- Ro10-5824
- Ropinirole
- Rotigotine
- Roxindole
- Salvinorin A
- SKF-89,145
- Sumanirole
- Terguride
- Umespirone
- WAY-100,635
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|