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Although cocaine binds to the DAT, SERT, and NET with ≈ equal affinity, the behavioral reinforcing and psychostimulant properties of this drug, in animals, is most strongly latched onto its ability to bind to the DAT, elevating the level of supracellular DA throughout the synapse, which is then free to go on and interact with a range of receptors, and other molecular targets, in a dose dependent manner (M. Ritz, et al. 1987).[1] It is also possible that cocaine can bind to GPCRs directly, triggering specific biochemical cascade reactions, which are unique to cocaine.

Phenyltropanes (PT's) are normally made from cocaine, although they are stronger, and more robust, and can be easily modified to maximize DAT specificity, e.g. RTI-113 (Wilcox, et al. 2002).[2] A number of articles are available free of charge from the L. Howard website, which are certainly worth reading. Speed of onset and other timing considerations also impact on the propensity for repeat administration; crack, for example, is most addictive (W. Woolverton, et al. 2004),[3] (S. Wee, et al. 2007).[4] Phenyltropanes have been researched extensively, because they are thought to harbor useful medicinal properties, particularly in treating addiction,[5] Parkinson's disease (Madras, et al. 2006),[6] and ADHD,[7] although none of them have actually surfaced into the mainstream yet. The following article provides a condensed overview of PT's. For indepth coverage, the reader should consult the references. Psychostimulants have euphoric and alerting properties that suggest their usefulness in treating depressive disorders; however, problems with tolerance and dependence with some drugs "militate" against their widespread therapeutic use where more acceptable licensed alternatives are available (Orr and Taylor, 2007).[8]

PT Diastereoisomer SAR

R. Clarke, et al. originally set out to separate the stimulant actions of cocaine from its toxicity and dependence liability (F. Carroll, 2003).[9] These compounds are CNS stimulants. Early studies demonstrated DAT in vitro binding can be strengthened via phenyl nucleus p-H replacement (F. Carroll, et al. 1991).[10] In rat cocaine-discrimination tests, RTI-31 and RTI-32 were ~26 x and ~6 x more potent than cocaine, respectively (Balster, et al. 1991).[11] This finding has led researchers to question if DAT binding alone is sufficient in accounting for PT's in vivo activity. Infact, it has recently been proven in vitro, that RTI-31 elicits potent muscarinic activity. Also, the hydrophilic catechol entity resulted in decreased activity, suggesting that the choice of substituents must be suitably lipophilic, to impart high potency upon the resultant compounds (P. Meltzer, et al. 2003).[12] As the size of the p-moiety increases, the conditions required for SERT inhibition become favorable, and it is even possible to achieve a high level of selectivity for this transporter if and when the p-function becomes sufficiently inflated.[13][14] The (1R,2S,3S) isomers are a central focal point in PT research, because these are far-superior to the (1R,2R,3S) conformation. Brasofensine,[15][16] and tesofensine,[17] possess (1R,2R,3S) diastereochemistry though. This was one of the motivations, for further investigating other simple p-substituted diastereoisomers, alongside the (1R,2S,3S) isomers, to gain a deeper mechanistical understanding into how tropane framework dynamism influences the MAT binding and behavioral activities, of the resultant molecules. The other PT diastereoisomer variations include the (1R,2R,3S) and (1R,2S,3R) layouts, although the latter is not immediately derived from alkylecgonidine, and employs a forced synthetic pathway. The (1R,2R,3R) outlay did not reach statistical significance, and was omitted for clarity. The MAT IC50, gross behaviour (GB), mice LMA, and cocaine-trained rat discrimination data, for a variety of PT isomer variations, is disclosed (F. Ivy Carroll, et al. 2004).[18]

MAT Binding

  • All the compounds have DAT IC50 values exceeding SERT/NET affinity, but in the case of RTI-51/55 the SERT Ki values attain <1nM.
Monoamine Transporter Binding Properties of 2-Carbomethoxy-3-p-Substituted-Phenyltropanes
Identification Marker DAT / NET / SERT IC50, nM (K, nM) IC50 ÷ Ki Uptake Ratio
Compound X [3H]CFT [3H]Nisoxetine [3H]Paroxetine NET SERT NE ÷ DA SER ÷ DA SER ÷ NE
WIN-35,065-2H23 ± 5920 ± 70 (550 ± 44)1960 ± 61 (178 ± 5.5)1.67311.014085.222.130
WIN 35,428F13.9 ± 2.0835 ± 45 (503 ± 27)692 ± 27 (63 ± 2.5)1.66010.9860.0749.78.8289
RTI-31Cl1.1 ± .137 ± 2.1 (22 ± 1.3)44.5 ± 1.3 (4.0 ± .12)1.68211.1333.6440.451.203
RTI-51Br1.7 ± .237.4 ± 5.2 (23 ± 3.1)10.6 ± .24 (.96 ± .02)1.62611.04226.235.2834
RTI-55I1.3 ± .0136 ± 2.7 (22 ± 1.6)4.21 ± .30 (.38 ± .03)1.63611.0827.693.24.1169
RTI-32Me1.7 ± .360 ± .53 (36 ± .32)240 ± 27 (23 ± 2.5)1.66710.4335.29141.24.000
2aH101 ± 16541 ± 69 (271 ± 34)5700 ± 720 (518 ± 66)1.99611.005.35656.4410.54
2bF21.0 ± .51200 ± 90 (741 ± 55)5060 ± 490 (460 ± 44)1.61911.0057.14241.04.217
2cCl3.1 ± .65.14 ± 1.08 (3.1 ± .60)53 ± 3 (4.8 ± .26)1.6611.041.65817.1010.31
2dBr1.7 ± .432.4 ± 3.5 (16.2 ± 1.7)84 ± 13.5 (20.6 ± 3.3)2.0004.07819.0649.412.593
2eI2.9 ± .252.4 ± 4.9 (32 ± 2.0)64.9 ± 1.97 (5.9 ± .18)1.63811.0018.0722.381.239
2fMe10.2 ± .8270 ± 24 (160 ± 14)4250 ± 420 (390 ± 38)1.68810.9026.47416.715.74
3aH670 ± 90>10000>10000
3bF325 ± 87200 ± 810 (4340 ± 480)>100001.65922.15
3cCl25.0 ± 5444 ± 29 (222 ± 15)1450 ± 160 (356 ± 40)2.0004.07317.7658.003.266
3dBr15.7 ± .9272 ± 25 (136 ± 15)570 ± 80 (140 ± 20)2.0004.07117.3436.312.100
3eI22.7 ± .9760 ± 49 (458 ± 30)66.3 ± 1.8 (6.0 ± .16)1.65911.0533.482.921.087
3fMe207 ± 212230 ± 380 (1120 ± 190)>100001.99110.77
  • DAT arrangement of diastereoisomer potency: (1R,2S,3S) > (1R,2S,3R) > (1R,2R,3S).
  • WIN 35,428 and 2b possess the greatest NE/DA selectivity. RTI-32 and 2f have the greatest 5-HT/DA selectivity.

LMA, 2D and GB effects

The (1R,2S,3S) isomers are much stronger than any of the trans compounds.


In conclusion, the (1R,2S,3S) isomers are far superior to the other diastereoisomers, in the context of therapeutic treatment regimes.

Reduced Rate of In Vivo DAT Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants (S. Wee, et al. 2006).[19]

In the above study, the effects of cocaine, WIN 35,428, RTI-31 and RTI-51 drugs were compared in nonhuman primates.
RTI-31 has pronounced muscarinic activity.

There is evidence that the (1R,2R,3S) isomers may be potent Na+ channel blockers? (Reith, 1986).[20]

WIN 35,428 and Mazindol Are Mutually Exclusive in Binding to the Cloned Human Dopamine Transporter

Disubstituted PT's

Early studies demonstrated that dual substituted (1R,2S,3S) methoxycarbonyl p,m-PT's exhibit DAT binding affinity superior to the simple monosubstituted PT's. For example, RTI-111 and RTI-112 were the first PT's reported to show DAT binding <1nM.[21][22] Not long afterwards, it was shown that they also possess <1nM SERT affinity.[23] This is an important aspect of these compounds, since serotonin indirectly modulates nucleus accumbens dopamine release.

Importantly, since animal behavior studies have demonstrated that SSRIs as well as SDARIs can attenuate cocaine-induced stimulant and reinforcing effects, compounds displaying both ↑ DAT and ↑ SERT affinity, are of particular interest (F. Carroll, et al. 2005).[24]

MAT Binding Properties of New p,m-Disubstituted (1R,2S,3S) Methoxycarbonyl Phenyltropanes
Identification Marker DAT / SERT / NET IC50, nM (K, nM) IC50 ÷ Ki Uptake Ratio
Compound Y Z [3H]WIN 35,428 [3H]Paroxetine [3H]Nisoxetine SER NE SER/DA NE/DA NE/5HT
RTI-111ClCl.79 ± .083.13 ± .36 (.29 ± .03)18 ± .85 (11 ± .51)10.791.6363.96222.785.751 (37.93)
RTI-112ClMe.82 ± .0510.5 ± .41 (.95 ± .04)36.2 ± 1.02 (21.8 ± .62)11.051.66112.8044.153.448 (22.95)
ClBr.42 ± .02.78 ± .04 (.19 ± .01)7.24 ± .69 (3.62 ± .34)4.10521.85717.249.282 (19.05)
ClI.41 ± .091.39 ± .23 (.34 ± .06)15.1 ± .59 (7.74 ± .29)4.0881.9513.39036.8310.86 (22.76)
BrCl.12 ± .04.94 ± .09 (.23 ± .02)1.31 ± .13 (.65 ± .07)4.0872.0157.83310.921.394 (2.826)
BrBr.27 ± .01.71 ± .03 (.18 ± .01)2.80 ± .16 (1.10 ± .08)3.9442.5452.63010.373.944 (6.111)
BrI.21 ± .061.14 ± .26 (.25 ± .04)10.4 ± 1.5 (5.12 ± .77)4.562.0315.42949.529.123 (20.48)
ICl.26 ± .051.04 ± .14 (.63 ± .05)1.26 ± .09 (.63 ± .05)1.651244.8461.212 (2)
IBr.20 ± .04.58 ± .07 (.14 ± .02)1.96 ± .17 (.98 ± .09)4.14322.99.83.379 (7)
II.98 ± .052.0 ± .56 (.19 ± .05)40.4 ± 3.56 (24 ± 2.1)10.531.6832.04141.2220.2 (126.3)
MeMe.43 ± .079.88 ± 1.11 (2.42 ± .27)107 ± 11 (44 ± 4.7)4.0832.43222.98248.810.83 (18.18)

DAT: (p-Br, m-Cl) < (p-I, m-Br) ≈ (p-Br, m-I) ~ (p-I, m-Cl) ≈ p,m-Br2 < (p-Cl, m-I) ≈ (p-Cl, m-Br) ≈ p,m-Me2 < p,m-Cl2 < (p-Cl, m-Me) < p,m-I2.

SERT: (p-I, m-Br) < p,m-Br2 ~ (p-Cl, m-Br) < (p-Br, m-Cl) ~ (p-I, m-Cl) < (p-Br, m-I) < (p-Cl, m-I) < p,m-I2 < p,m-Cl2 < (p-Cl, m-Me) < p,m-Me2.

NET: (p-I, m-Cl) ~ (p-Br, m-Cl) < (p-I, m-Br) < p,m-Br2 < (p-Cl, m-Br) < (p-Br, m-I) < (p-Cl, m-I) < p,m-Cl2 < (p-Cl, m-Me) < p,m-I2 < p,m-Me2.

RTI-112

RTI-112 has high DAT/SERT affinity. This compound significantly reduces rhesus monkeys cocaine consumption, even though it only functions as an unreliable reinforcer. PET studies revealed that in contrast to SDARI analogs such as RTI-113 and GBR-12909, RTI-112 shows no detectable DAT occupancy when dosed at its ED50 for reduction of cocaine. In contrast it highly occupies the SERT at this dose.

Effects of Dopamine Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys: Relationship to Transporter Occupancy Determined by Positron Emission Tomography Neuroimaging. (2004)

Non-aza-tropane analogs

It had been hypothesized that transporter binding of the tropanes might include ionic bonding of the central tropane nitrogen. But it turned out that at this site neither ionic nor hydrogen bonding is a prerequisite for potent monoamine reuptake inhibition. Oxa- and thia-analogs of RTI-111 are potent inhibitors, and even an N-replacement by methylene holds the potency within the same magnitude.[25] However, N-quarternisation ('N-dimethyl') considerably reduces DAT affinity.

Neurosearch

Neurosearch was founded by the inventor of Paxil (Christensen; Jorgen Anders (Virum, DK)). Amusingly, some tropane-based Paxil compounds have been prepared and shown to be good DAT blockers. In 1994 Neurosearch made the original and unrivaled claim that certain (1R,2R,3S)-phenyltropanes can be made to possess tantalizing biochemical activity, although it is imperative that the selection of pharmacophores, on the 2,3-positions of the 8-azabicyclo[3.2.1]octane ring, is made appropriately. This revolutionary early finding has allowed Neurosearch to deliberate on inventing some innovative spin-out compounds, which have been remarkably well tolerated, and have now entered into the phase of being shelled out to humans, and not just restricted to NHP based animal experiments. This is the only company believed to be actively pursuing phenyltropanes in the context of ongoing clinical evaluations, which makes studying these compounds very important.

Brasofensine (NS-2214) and tesofensine (NS2330) are representative examples in this series, although it should be stressed that the methoxymethyl group (desoxy–O=COMe) is also a likely candidate, for future development. These compounds have the desired triple mode of action. Whereas brasofensine has been closely linked-up with Parkinson's, tesofensine is believed to have properties that make it a desirable slimming agent, with uses in the treatment of obesity. Hence, these molecules have useful medicinal applications, and are not just being pursued for recreational purposes.

File:BTfensine.GIF

2-Position N DAT IC50 (nM) NAT IC50 (nM) SERT IC50 (nM) In vivo ED50 (mg/kg) In vitro IC50 (μM)
MeO-CH2Me10210 n.d..015
EtOCH2Me83.211n.d..035
PhSCH2Me4.32.89.2n.d.n.d.
MeO-N=CHMe,sulfate31.313.90.0030
MeO-N=CHH2Cl21.31.7 1.4.006
syn MeO-N=CHMe3.41.5n.t.37.0018

The following rating scale is used for the high intensity stereotypy on the condition that the behavioural syndromes are as described above:

+=only stereotyped sniffing ++=stereotyped sniffing and episodic licking +++=continuous licking and/or biting gnawing Compound (1R,2R,3S)-3-(p,m-Dichlorophenyl)tropane-O-methyl-aldoxime Dose(p.o.) Activity 15 mg/kg +++ is the lowest "dosis" giving the activity indicated.

Brasofensine, which has the 2α,3β-stereochemistry, was reported to be less potent than its 2β,3β-isomer in both DAT in vitro and in vivo binding assays. Nevertheless, brasofensine is reported to show excellent efficacy, with a favorable adverse effect profile after oral administration in relevant animal models of Parkinson’s disease. In addition, a clinical study designed to investigate the safety of brasofensine in patients receiving levadopa/carbidopa treatment indicated that no serious adverse effects were experienced at doses of 0.5-4.0 mg/d (Scott, 2006).[26]

Nortropanes

Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifoxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression (F. Ivy Carroll & Sameer Tyagi, 2005).[27]

It was already establised that enhanced –ve electrostatic field energy around the p-area is conducive towards MAT binding. N-demethylation has the effect of dramatically improving NE/5HT activity, but does not leave a significant DAT footprint (Bruce E. Blough, Philip Abraham).[28] N-demethylation occurs naturally under physiological circumstances, although hydrolysis of the ester is likely to be the predominant mode of degradation in vivo. None the less, these are valuable research tools.

Transporter Binding Affinities for p-Hydrocarbon Nor/Tropanes.
RTI X N [3H]Paroxetine [3H]WIN 35,428 [3H]Nisoxetine DA ÷ 5HT NE ÷ 5HT NE ÷ DA
83EthylMe28.4 ± 3.855 ± 24030 ± 3811.93773.27141.9
173H8.13 ± .3049.9 ± 7.3122 ± 126.1382.44515.01
282n-PropylMe70.4 ± 4.168.5 ± 7.13920 ± 130.973057.2355.68
364H26 ± 1.3212 ± 17532 ± 8.18.1542.50920.46
302isopropylMe191 ± 9.5597 ± 5275K ± 58203.126125.6392.7
330H15.1 ± .97310 ± 21ND20.53
359HC=CH2Me9.5 ± .81.24 ± .278 ± 4.1.130562.908.211
309H2.25 ± .171.73 ± .0514.9 ± 1.18.76898.6136.622
283Me-C=CH2Me3.13 ± .1614.4 ± .301330 ± 3334.60192.36424.9
357H0.6 ± .0623 ± .9144 ± 1238.336.261240
296trans-
internallyl
Me11.4 ± .285.29 ± .531590 ± 93.4640300.6139.5
368H1.3 ± .128.6 ± 3.154 ± 16221.88841.54
304syn-
internallyl
Me7.09 ± .7115 ± 1.22800 ± 3002.116186.7394.9
358H1.15 ± .131.6 ± 2.2147 ± 4.324.484.652127.8
301termallylMe28.4 ± 2.432.8 ± 3.12480 ± 2291.15575.6187.32
369H6.2 ± .356.5 ± 5.689.7 ± 9.69.1131.58814.47
360C≡CHMe4.4 ± .41.2 ± .183.2 ± 2.8.272769.3318.91
305H1.59 ± .21.24 ± .1121.8 ± 1.0.779917.5813.71
281C≡CMeMe15.7 ± 1.52.37 .2820 ± 46.1510346.052.23
307H3.16 ± .336.11± .67116 ± 5.11.93418.9936.71

Heterocycles and Amides

It is hoped that these will be to cocaine, what methadone is to heroin, or what bupropion is to tobacco.
Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse (F. Ivy Carroll, et al. 2006).[29]

File:HeteroCD.GIF

DARI Heterocycles
Identification Marker DAT / NET / SERT IC50, nM (K, nM) Uptake Ratio
Compound X R [3H]WIN 35,428 [3H]Nisoxetine [3H]Paroxetine NE ÷ DA SER ÷ DA
Cocaine--89.13298 (1986)1045 (45)37.0111.79
RTI-177Clphenyl1.28504 (304)2420 (220)393.81891
RTI-176Mephenyl1.58398 (239)5110 (465)251.93234
RTI-354Meethyl1.62299 (180)6400 (582)184.63951
RTI-336Clp-Me-phenyl4.091714 (1033)5741 (522)419.11404
RTI-386Mep-MeO-phenyl3.93756 (450)4027 (380)192.41025

Although the heterocycle has the effect of increasing both metabolic stability and DAT selectivity, careful selection is needed to ensure good potency, esp. when taking into account critical factors, inc. the economy and efficacy of drug molecules, with environmental considerations to boot. RTI-177 seems to have a good duration span, whereas some of the other analogs in this series do not appear to be credibly superior to the parent ester compounds from which they are derived. However, the potency of RTI-177 is insufficient for it to be regarded as a suitable candidate molecule, worthy of pursuing into the scale-up stages of pilot plant projects. There are, however, suitable alternatives. The dimethyl, pyrrolidino and morpholino amides are all representative examples of how the sidechain can be modified so that the resultant molecules can be made more metabolically stable. The reference at the top of this section includes details of such content, although animal data is lacking.

Patents

Clarke Patent[30] Ivy Carroll Patents[31][32][33][34] Kozikowski Patents[35][36][37][38] Kuhar Patents[39][40][41][42][43][44] 5834484
NES: Trans,[45] Brasofensine,[46] Tesofensine (NS2330),[47][48]

External links

References

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  2. [2]Self-administration of cocaine and the cocaine analog RTI-113: Relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys. Wilcox, K.M., Lindsey, K.P., Votaw, J.R., Goodman, M.M., Martarello, L., Carroll, F.I. and Howell, L.L. Synapse, 43: 78-85, 2002.
  3. [3]Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine. William L. Woolverton and Zhixia Wang. European Journal of Pharmacology, Volume 486, Issue 3, 23 February 2004, Pages 251-257.
  4. [4]Effects of Dose and Session Duration on Cocaine Self-Administration in Rats. Sunmee Wee, Sheila E. Specio, and George F. Koob. J. Pharmacol. Exp. Ther. 2007 320: 1134-1143.
  5. [5] NEURAL MECHANISMS OF ADDICTION: The Role of Reward-Related Learning and Memory. Steven E. Hyman, ­ Robert C. Malenka, and ­ Eric J. Nestler. Annual Review of Neuroscience, Vol. 29: 565-598 (July 2006).]
  6. [6] Dopamine Transporter (DAT) Inhibitors Alleviate Specific Parkinsonian Deficits in Monkeys: Association with DAT Occupancy in Vivo. B. K. Madras, M. A. Fahey, M. Goulet, Z. Lin, J. Bendor, C. Goodrich, P. C. Meltzer, D. R. Elmaleh, E. Livni, A. A. Bonab, and A. J. Fischman. J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 570 - 585.
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  9. [9]2002 Medicinal Chemistry Division Award Address: Monoamine Transporters and Opioid Receptors. Targets for Addiction Therapy Carroll, F. I. J. Med. Chem. 2003; 46(10); 1775-1794.
  10. [10]F. Ivy Carroll, Yigong Gao, M. Abdur Rahman, Philip Abraham, Karol Parham, Anita H. Lewin, John W. Boja, Michael J. Kuhar J. Med. Chem.; 1991; 34(9); 2719-2725.
  11. [11]Drug and Alcohol Dependence, V29, Issue 2, 1991, pp 145-151
  12. [12]Bioorganic & Medicinal Chemistry Letters Volume 13, Issue 22, 17 November 2003, Pages 4133-4137
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  19. [19]A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants. Sunmee Wee, F Ivy Carroll and William L Woolverton. Neuropsychopharmacology, (2006), 31, 351–362.
  20. [20]Structural requirements for cocaine congeners to interact with [3H]batrachotoxinin A 20-alpha-benzoate binding sites on sodium channels in mouse brain synaptosomes J. Biol. Chem. 1986 261: 7300-7305.
  21. [21]F. Ivy Carroll, S. Wayne Mascarella, Michael A. Kuzemko, Yigong Gao, Philip Abraham, Anita H. Lewin, John W. Boja, Michael J. Kuhar. J. Med. Chem.; 1994; 37(18); 2865-2873.
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  24. [24]Synthesis and Monoamine Transporter Binding Properties of 3-(3',4'-Disubstituted phenyl)tropane-2-carboxylic Acid Methyl Esters. F. Ivy Carroll, Bruce E. Blough, Zhe Nie, Michael J. Kuhar, Leonard L. Howell, and Hernan A. Navarro. J. Med. Chem.; 2005; 48(8) pp 2767 - 2771
  25. a) [25] Synthesis of 8-thiabicyclo[3.2.1]octanes and Their Binding Affinity for the Dopamine and Serotonin Transporters. Pham-Huu D-P, Deschamps JR, Liu S, Madras BK, Meltzer PC, Bioorg Med Chem. 2007, 15(2): 1067–82. PMID 17070057
    b) PMID 14612136 Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors. Madras BK et al. Eur J Pharmacol. 2003; 479(1-3): 41-51. c) Compare PMID 11746710 Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates? Goulet M, Miller GM, Bendor J, Liu S, Meltzer PC, Madras BK. Synapse 2001, 42(3): 129-40.
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  27. [27]Synthesis and Monoamine Transporter Binding Properties of 3-(Substituted phenyl)nortropane-2-carboxylic Acid Methyl Esters. Norepinephrine Transporter Selective Compounds. F. Ivy Carroll, Sameer Tyagi, Bruce E. Blough, Michael J. Kuhar, and Hernn A. Navarro. J. Med. Chem.; 2005; 48(11) pp 3852 - 3857.
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  30. United States Patent 3,813,404 Issue Date: May 28, 1974
  31. United States Patent 6,329,520 Carroll, et al. December 11, 2001
  32. United States Patent 6,123,917 Carroll September 26, 2000
  33. United States Patent 5,736,123 Carroll April 7, 1998
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  38. United States Patent 6,982,271 Kozikowski, et al. Tropane analogs
  39. United States Patent 6,531,483 Kuhar, et al. March 11, 2003
  40. United States Patent 6,358,492 Kuhar, et al.
  41. United States Patent 5,935,953 Kuhar, et al. August 10, 1999
  42. United States Patent 5,496,953 Kuhar, et al.
  43. United States Patent 5,413,779 Kuhar, et al. May 9, 1995
  44. United States Patent 5,380,848 Kuhar, et al. January 10, 1995
  45. US Patent 5,374,636 Moldt, et al. 1994. 2,3-trans-disubstituted tropane compounds which have useful pharmaceutical utility.
  46. United States Patent 5,736,556 Moldt, et al. April 7, 1998 Tropane-2-aldoxime derivatives as "nevro" transmitter reuptake inhibitors
  47. United States Patent 6,288,079 Scheel-Kruger,et al. September 11, 2001
  48. United States Patent 6,395,748 Scheel-Kruger, et al. May 28, 2002

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