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JZ-IV-10
Systematic (IUPAC) name
(+)-2-([(3R,4S)-1-methyl-4-(4-chlorophenyl)piperidin-3-yl]methylthio)-N-isopropylacetamide
Identifiers
ATC code  ?
PubChem 11291199
Chemical data
Formula C18H27ClN2OS 
Mol. mass 354.937 g/mol
SMILES eMolecules & PubChem
Therapeutic considerations
Pregnancy cat.  ?
Legal status

JZ-IV-10 ("compound 16e") 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
Triplemode.gif
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 are do not function as robust reinforcers.[5]

References

  1. ^ WO patent 2005041875
  2. ^ 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 medicinal chemistry 47 (24): 5821–5824. doi:10.1021/jm040117o. PMID 15537337.  edit
  3. ^ 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
  4. ^ 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
  5. ^ 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
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