User:Nuklear/Phenyltropane

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Contents

[edit] Introduction

Cocaine binds to the DAT, SERT, and NET with ≈ equal affinity, but the behavioral reinforcing and psychostimulant properties of this drug, in animals, is most strongly consonent with its ability to elevate supracellular DA concentrations throughout the synapse (M. Ritz, et al. 1987).[1] Interestingly, DAT knockout (KO) mice, in which random genetic mutations are used to render the DAT incapable of clearing extracellular DA reserves, still self-administered cocaine reliably.[cit] This led to speculation that the SERT and NET actions of cocaine may, at least partially, account for the behavioral reinforcing actions of this drug.[cit] Inother words cocaine possesses redundant reward pathways. This has been a controversial hypothesis, that is only as reliable as the experimental data used to support it. More recently, DAT knock-in mice have been developed, to further test this hypothesis.[cit] DAT knock-in mice differ from KO mice in that the the cocaine recognition site has been mutated in such a way that it is no longer cocaine sensitive, although the DAT is still partially or fully able to clear DA from the synaptic cleft. Importantly, the DAT knock-in strain of mice would not self-administer cocaine, reinstating the earlier hypothesis that the DAT is the critical recognition site for cocaine. Although all drugs of abuse differ in their behavioral modes of action, crucially either directly or indirectly, it is believed that they share the common property of being able to converge onto DA signaling pathways (Nestler). For this reason, drugs that modulate neuronal dopaminergic terminals are the central focus of treatment agents in the substance addiction field. Likewise, dopaminergic pathways are also activated by natural reinforcers including food, sex, exercise and pathological gambling.

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]

[edit] Leonard Howell & Co-Workers

The link provided gives references to some of the online material that is available free of charge. http://research.yerkes.emory.edu/Howell/publications.html

The QSAR provides us with information for each of the analogs in terms of potency and ratio of affinity for the DA/NE/5-HT transporters. That is the medicinal chemistry and pharmalogical side of the equation. On securing this information, the next step is to consider using the analogs for behavioral studies. Understandably there is ethical issues surrounding the use of these compounds on humans, and studies on rodents provides limited information. The next step then, it to study the actions of cocaine and these compounds on non-human primates.

In reading the attached references, a number of interesting observations become apparent to the reader:

In order for the behaviorally reinforcing actions of cocaine and related analogs to reach manifest, a high DAT occupancy is necessary. Cocaine is a SNDRI and the optimal DAT occupancy for self-administration is 60% with this drug. Much higher DAT occupancies can be achieved with some of the more selective DARI ligands such as RTI-113. What is interesting here though is that although these drugs acheive a higher DAT occupancy than cocaine due to their high DAT specificity, these drugs were not stronger than cocaine in eliciting self-administration in the animals. What this demonstrates is that simple DAT occupancy is unlikely to be the only factor in determining self-administration propensity.

Another interesting observation is that although cocaine has perhaps the strongest propensity for self-administration out of all psychostimulants, it is only moderate in terms of its potency. What this tells us is that simple affinity of a given analog for the monoamine transporter pumps is not a prediction of the efficacy for behavioral reinforcement.

The next point is that SSRIs decrease the self-administration of cocaine.

[edit] 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 is an interesting observation in view of the fact that RTI-31 and RTI-32 both possible a comparible binding affinity to the DAT. This discrepancy in values between pharmacological data and behavioral effects 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]

  • The in vitro MAT binding affinity of the "alpha,alpha" PT's was actually farily reasonable. However, in behavioral tests, both isomers were inactive up to 100mg/kg, where they caused death at this dose. Therefore their disinclusion seems appropriated.

[edit] 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-35,065-2 H 23 ± 5 920 ± 70 (550 ± 44) 1960 ± 61 (178 ± 5.5) 1.673 11.01 40 85.22 2.130
WIN 35,428 F 13.9 ± 2.0 835 ± 45 (503 ± 27) 692 ± 27 (63 ± 2.5) 1.660 10.98 60.07 49.78 .8289
RTI-31 Cl 1.1 ± .1 37 ± 2.1 (22 ± 1.3) 44.5 ± 1.3 (4.0 ± .12) 1.682 11.13 33.64 40.45 1.203
RTI-51 Br 1.7 ± .2 37.4 ± 5.2 (23 ± 3.1) 10.6 ± .24 (.96 ± .02) 1.626 11.04 22 6.235 .2834
RTI-55 I 1.3 ± .01 36 ± 2.7 (22 ± 1.6) 4.21 ± .30 (.38 ± .03) 1.636 11.08 27.69 3.24 .1169
RTI-32 Me 1.7 ± .3 60 ± .53 (36 ± .32) 240 ± 27 (23 ± 2.5) 1.667 10.43 35.29 141.2 4.000
2a H 101 ± 16 541 ± 69 (271 ± 34) 5700 ± 720 (518 ± 66) 1.996 11.00 5.356 56.44 10.54
2b F 21.0 ± .5 1200 ± 90 (741 ± 55) 5060 ± 490 (460 ± 44) 1.619 11.00 57.14 241.0 4.217
2c Cl 3.1 ± .6 5.14 ± 1.08 (3.1 ± .60) 53 ± 3 (4.8 ± .26) 1.66 11.04 1.658 17.10 10.31
2d Br 1.7 ± .4 32.4 ± 3.5 (16.2 ± 1.7) 84 ± 13.5 (20.6 ± 3.3) 2.000 4.078 19.06 49.41 2.593
2e I 2.9 ± .2 52.4 ± 4.9 (32 ± 2.0) 64.9 ± 1.97 (5.9 ± .18) 1.638 11.00 18.07 22.38 1.239
2f Me 10.2 ± .8 270 ± 24 (160 ± 14) 4250 ± 420 (390 ± 38) 1.688 10.90 26.47 416.7 15.74
3a H 670 ± 90 >10000 >10000 — —
3b F 325 ± 8 7200 ± 810 (4340 ± 480) >10000 1.659 — 22.15
3c Cl 25.0 ± 5 444 ± 29 (222 ± 15) 1450 ± 160 (356 ± 40) 2.000 4.073 17.76 58.00 3.266
3d Br 15.7 ± .9 272 ± 25 (136 ± 15) 570 ± 80 (140 ± 20) 2.000 4.071 17.34 36.31 2.100
3e I 22.7 ± .9 760 ± 49 (458 ± 30) 66.3 ± 1.8 (6.0 ± .16) 1.659 11.05 33.48 2.921 .087
3f Me 207 ± 21 2230 ± 380 (1120 ± 190) >10000 1.991 — 10.77
  • 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.

[edit] 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

[edit] 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-111 Cl Cl .79 ± .08 3.13 ± .36 (.29 ± .03) 18 ± .85 (11 ± .51) 10.79 1.636 3.962 22.78 5.751 (37.93)
RTI-112 Cl Me .82 ± .05 10.5 ± .41 (.95 ± .04) 36.2 ± 1.02 (21.8 ± .62) 11.05 1.661 12.80 44.15 3.448 (22.95)
Cl Br .42 ± .02 .78 ± .04 (.19 ± .01) 7.24 ± .69 (3.62 ± .34) 4.105 2 1.857 17.24 9.282 (19.05)
Cl I .41 ± .09 1.39 ± .23 (.34 ± .06) 15.1 ± .59 (7.74 ± .29) 4.088 1.951 3.390 36.83 10.86 (22.76)
Br Cl .12 ± .04 .94 ± .09 (.23 ± .02) 1.31 ± .13 (.65 ± .07) 4.087 2.015 7.833 10.92 1.394 (2.826)
Br Br .27 ± .01 .71 ± .03 (.18 ± .01) 2.80 ± .16 (1.10 ± .08) 3.944 2.545 2.630 10.37 3.944 (6.111)
Br I .21 ± .06 1.14 ± .26 (.25 ± .04) 10.4 ± 1.5 (5.12 ± .77) 4.56 2.031 5.429 49.52 9.123 (20.48)
I Cl .26 ± .05 1.04 ± .14 (.63 ± .05) 1.26 ± .09 (.63 ± .05) 1.651 2 4 4.846 1.212 (2)
I Br .20 ± .04 .58 ± .07 (.14 ± .02) 1.96 ± .17 (.98 ± .09) 4.143 2 2.9 9.8 3.379 (7)
I I .98 ± .05 2.0 ± .56 (.19 ± .05) 40.4 ± 3.56 (24 ± 2.1) 10.53 1.683 2.041 41.22 20.2 (126.3)
Me Me .43 ± .07 9.88 ± 1.11 (2.42 ± .27) 107 ± 11 (44 ± 4.7) 4.083 2.432 22.98 248.8 10.83 (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.

[edit] 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)

Also, note that RTI-112 has nicotinic acetylcholine receptor activity (c.f. bupropion).

[edit] 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.

[edit] 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.

Image:BTfensine.GIF

2-Position N DAT IC50 (nM) NAT IC50 (nM) SERT IC50 (nM) In vivo ED50 (mg/kg) In vitro IC50 (μM)
MeO-CH2 Me 10 2 10 n.d. .015
EtOCH2 Me 8 3.2 11 n.d. .035
PhSCH2 Me 4.3 2.8 9.2 n.d. n.d.
MeO-N=CH Me,sulfate 3 1.3 13 .90 .0030
MeO-N=CH H2Cl 2 1.3 1.7 1.4 .006
syn MeO-N=CH Me 3.4 1.5 n.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]

[edit] 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.

Although not apparent from the attached table, one needs to bear in mind that nortropanes have an increased seizure risk relative to their N-methyl parent compounds. This needs to be taken into account if considering this synthetic strategy as a viable approach to obtaining behaviorally active compounds with a more balanced DAT/NET/SERT affinity ratio.

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
83 Ethyl Me 28.4 ± 3.8 55 ± 2 4030 ± 381 1.937 73.27 141.9
173 H 8.13 ± .30 49.9 ± 7.3 122 ± 12 6.138 2.445 15.01
282 n-Propyl Me 70.4 ± 4.1 68.5 ± 7.1 3920 ± 130 .9730 57.23 55.68
364 H 26 ± 1.3 212 ± 17 532 ± 8.1 8.154 2.509 20.46
302 isopropyl Me 191 ± 9.5 597 ± 52 75K ± 5820 3.126 125.6 392.7
330 H 15.1 ± .97 310 ± 21 ND 20.53 — —
359 HC=CH2 Me 9.5 ± .8 1.24 ± .2 78 ± 4.1 .1305 62.90 8.211
309 H 2.25 ± .17 1.73 ± .05 14.9 ± 1.18 .7689 8.613 6.622
283 Me-C=CH2 Me 3.13 ± .16 14.4 ± .30 1330 ± 333 4.601 92.36 424.9
357 H 0.6 ± .06 23 ± .9 144 ± 12 38.33 6.261 240
296 trans-
internallyl		 Me 11.4 ± .28 5.29 ± .53 1590 ± 93 .4640 300.6 139.5
368 H 1.3 ± .1 28.6 ± 3.1 54 ± 16 22 1.888 41.54
304 syn-
internallyl		 Me 7.09 ± .71 15 ± 1.2 2800 ± 300 2.116 186.7 394.9
358 H 1.15 ± .1 31.6 ± 2.2 147 ± 4.3 24.48 4.652 127.8
301 termallyl Me 28.4 ± 2.4 32.8 ± 3.1 2480 ± 229 1.155 75.61 87.32
369 H 6.2 ± .3 56.5 ± 5.6 89.7 ± 9.6 9.113 1.588 14.47
360 C≡CH Me 4.4 ± .4 1.2 ± .1 83.2 ± 2.8 .2727 69.33 18.91
305 H 1.59 ± .2 1.24 ± .11 21.8 ± 1.0 .7799 17.58 13.71
281 C≡CMe Me 15.7 ± 1.5 2.37 .2 820 ± 46 .1510 346.0 52.23
307 H 3.16 ± .33 6.11± .67 116 ± 5.1 1.934 18.99 36.71

[edit] 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]

Image: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 - - 89.1 3298 (1986) 1045 (45) 37.01 11.79
RTI-177 Cl phenyl 1.28 504 (304) 2420 (220) 393.8 1891
RTI-176 Me phenyl 1.58 398 (239) 5110 (465) 251.9 3234
RTI-354 Me ethyl 1.62 299 (180) 6400 (582) 184.6 3951
RTI-336 Cl p-Me-phenyl 4.09 1714 (1033) 5741 (522) 419.1 1404
RTI-386 Me p-MeO-phenyl 3.93 756 (450) 4027 (380) 192.4 1025

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.

[edit] 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]


[edit] References

  1. ^ [1]Cocaine receptors on dopamine transporters are related to self-administration of cocaine. MC Ritz, RJ Lamb, Goldberg SR, and MJ Kuhar. Science, 1987: Vol. 237. no. 4819, pp. 1219 - 1223.
  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.
  7. ^ [7] Dopamine genes and attention-deficit hyperactivity disorder: a review. J Psychiatry Neurosci. 2003 January; 28(1): 27–38.
  8. ^ [8]Orr, Katy; Taylor, David. CNS Drugs, Volume 21, Number 3, 2007 , pp. 239-257(19)
  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
  13. ^ [13]Bioorganic & Medicinal Chemistry Letters Volume 14, Issue 9, 3 May 2004, Pages 2117-2120
  14. ^ [14]Bioorganic & Medicinal Chemistry Letters Volume 15, Issue 4, 15 February 2005, Pages 1131-1133
  15. ^ [15]Curr Opin Investig Drugs. 2000 Dec;1(4):504-7.
  16. ^ [16]Ann Pharmacother 2002;36:225-230. DOI 10.1345/aph.1A152
  17. ^ [17]Br J Clin Pharmacol. 2007 February 22. Lehr T, Staab A, Tillmann C, Trommeshauser D, Raschig A, Schaefer HG, Kloft C.
  18. ^ [18]Monoamine Transporter Binding, Locomotor Activity, and Drug Discrimination Properties of 3-(4-Substituted-phenyl)tropane-2-carboxylic Acid Methyl Ester Isomers. Carroll, F. I.; Runyon, S. P.; Abraham, P.; Navarro, H.; Kuhar, M. J.; Pollard, G. T.; Howard, J. L. J. Med. Chem.; 2004; 47(25); 6401-6409.
  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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