JZ-IV-10

JZ-IV-10
	200px
Systematic (IUPAC) name
	(+)-2-([(3R,4S)-1-methyl-4-(4-chlorophenyl)piperidin-3-yl]methylthio)-N-isopropylacetamide
Identifiers
PubChem	CID 11291199
Chemical data
Formula	C18H27ClN2OS
Molar mass	354.937 g/mol[[Script error: No such module "String".]]
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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	Me	Ester	OMe	25 → 53	80 → 231	208 → 809
IV-22 → ?	H	Ester	OMe	10 → 31.1	114 → 107.8	170 → 774.9
IV-25 → IV-37	Me	Amide	NH₂	39 → 178	159 → 209	557 → 5790
	H		NH₂	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

File:Triplemode.gif

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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]

References

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↑ 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 medicinal chemistry. 47 (24): 5821–5824. doi:10.1021/jm040117o. PMC 1395211 Freely accessible. PMID 15537337. More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help) 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. More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help) edit
↑ Musachio, J.; Hong, J.; Ichise, M.; Seneca, N.; Brown, A.; Liow, J.; Halldin, C.; Innis, R.; Pike, V. (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. More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help) edit

[1] WO 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. PMC 1395211 Freely accessible. PMID 15537337. More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help) 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. More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help) edit

[4] Musachio, J.; Hong, J.; Ichise, M.; Seneca, N.; Brown, A.; Liow, J.; Halldin, C.; Innis, R.; Pike, V. (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. More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help) edit

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See also Sympathomimetic amines

JZ-IV-10

References

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