Phenyltropane

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Troparil: A structural analog of cocaine with omitted -COO- linkage - a parent compound of many MAT ligands (here in an unfavourable conformation of the O-Me. The methyl has to be at the other O, and trans). Phenyltropane.gif
Troparil: A structural analog of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands (here in an unfavourable conformation of the O-Me. The methyl has to be at the other O, and trans).

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. [2] [3] In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field,[ citation needed ] they are not the only researchers that have prepared these analogues. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

Contents

Uses

Addiction

The phenyltropane compounds were initially discovered by R. Clarke et al. during research to try and dissociate the stimulant properties of cocaine from its abuse and dependence liability. [4] [5] The first simple phenyltropanes to be made (WIN 35065-2 and WIN 34,428) were shown to be active in behavioral assays only for the ββ-isomers. The activity of the corresponding αβ-isomers was disappointing.

It was later shown that WIN 35065-2 and WIN 34,428 are mostly dopamine selective reuptake inhibitors with some residual actions at the norepinephrine transporter (NET) and serotonin transporter (SERT). The neurotransmitter dopamine is a key candidate for explanation of reinforcing actions drugs. [6] [7] It's unclear to which extent NET is involved in the reinforcing actions of cocaine (an SNDRI). [8] Animal studies show evidence that inhibiting the SERT might reduce cocaine intake. [9]

Animal studies on monkeys and rats have tried to assess the self-administration propensity of phenyltropane analogs alongside cocaine. Frequently the analogs are administered prior to the start of a session to see if they can suppress cocaine lever responding. Most of the analogs behave in ways that might be considered typical for a DRI. In particular, they tend to stimulate locomotor activity, and cause nonselective reductions in cocaine intake relative to food. [10] At the dose that can reduce cocaine intake, most of the analogs require a high DAT occupancy. [11] This would mean that the agonists would need to be behaviorally active at the dose that can bring about reductions in cocaine craving. Most of the analogs will readily substitute for cocaine, although most do not elicit as many lever responses per session because of pharmacokinetic factors. [12] Since these agonists function as reinforcers, there is an obvious concern surrounding their abuse liability.

Nevertheless, a slow onset, long-duration agonist seems like a reasonable approach. Phenyltropanes are widely used in animal studies of drug addiction as they share the stimulant properties and reinforcing effects of cocaine, but with higher potency, less non-specific binding which avoids the cardiotoxicity associated with cocaine. [13]

RTI336.png

RTI-336 is an interesting example of a phenyltropane that is being explored in the context of a treatment for cocaine addiction. [14] RTI-336 is a DRI and thus specifically targets the DAT which is responsible for the addictive properties of cocaine. Although there may be a role for NET inhibition and acetylcholinergic actions, clearly it is DA which is the critical neurotransmitter. Dopamine is a biological precursor to noradrenaline. DA is made from tyrosine, which is a non-essential amino acid given that it can be made from phenylalanine.

The more greatly attested habit creating methamphetamine is more serotonergic than the lesser reinforcing amphetamine. Most modern research suggests that 5-HT is negatively correlated with the addiction forming potential of psychostimulants, this is not saying that SRI properties cannot be considered beneficial. In fact, the above was proven by Rothman for releasing agents under the PAL-287 program of related molecules. What was somewhat interesting is that although the reason for the lack of reinforcement of RTI-112 is now well established, closely related RTI-111 was able to behave in ways that might be typical for a nonselective SNDRI such as cocaine. The role of the NET is not completely deleterious. In a recent paper by Rothman on transporter substrates, he establishes that for releasers that are amphetamine-like, discrimination stimulus is more accurately dictated by NE release than DA release. This argument does not mitigate a case against the importance of DA, but is suggestive that catecholamine in general is important. the exact ratio being 50:50 in the case of methylphenidate.

Desipramine and atomoxetine are not reliably self-administered though, whereas most selective DRIs are. SSRIs are not self-administered either. Hence, it should be borne in mind that these neurotransmitters are unlikely to be involved in the addiction forming properties of cocaine and related stimulants. Nevertheless, they are still behaviorally active and will contribute to the effects that such drugs elicit in their users.

Promiscuity among transporters is worth bearing in mind. Monoamine transporters can transport neurotransmitters other than their "native" neurotransmitter. [15] As an example, in the prefrontal cortex where DATs are lower in number, DA is transported mostly by the NET instead. Hence, selective NRIs such as atomoxetine are able to increase the concentration of supracellular (synaptic) DA in this brain region via NET blockade. [16]

Weeding out SERT and NET affinity is desirable in the context that these molecular targets are less relevant to the goals of the treatment program, which is to reduce cocaine intake. It can be clearly seen that RTI-336 has fewer metabolically labile sites than cocaine, and therefore has a longer duration span.

Binding ligands

These compounds are primarily used in scientific research, as their high binding affinity for monoamine transporters, and the wide range of radiolabelled phenyltropane compounds available with different binding specificities makes them very useful for mapping the distribution of the various monoamine transporters in the brain.

Other uses

Some phenyltropane derivatives have also been researched for medical use in the treatment of conditions such as Parkinson's disease [17] and Alzheimer's disease, depression, and their strong appetite suppressant effects makes them promising candidates for facilitating weight loss in the treatment of obesity.

Structure-activity relationships

Transporter selectivity

Compounds are known with a pronounced selectivity for each MAT – dopamine, [14] noradrenaline [18] and the serotonin transporter. [19]

Phenyltropane-based "SNDRI's" are another possibility. [2] [3]

Isomers study

All of the tables and graphs shown beneath is from an article published by FIC, et al. 2004. [20] In summary the following observations can be made: Troparil, WIN35428 and RTI-32 are insufficiently potent. This observation is mainly based on the fact that at 100 mg/kg both troparil and WIN35428 produce convulsions. The twist-boat isomers are insufficiently potent in all cases. The trans isomers (alpha,beta) are too weak and might actually be dangerous and cause death. RTI-55, while highly potent, still causes death at a dose of 100 mg/kg. It is advised to consider RTI-229. RTI-31 is the most potent isomers for the DAT and was "safe" (on a relative scale) even in the event of overdose at 100 mg/kg. RTI-51 also looks like a "good" compound, although its synthesis is slightly more difficult than for RTI-31. RTI-51 is less selective for the DAT than RTI-31 and has appreciable SERT affinity also.

Phenyltropaneisomers.png

MAT binding affinities

MAT IC50 (and Ki) of the 3 types of phenyltropane
RTIX[3H]CFT[3H]Nisoxetine[3H]ParoxetineNSN/DS/D
—H23 ± 5920 ± 70 (550 ± 44)1960 ± 61 (178 ± 5.5)1.7114085.2
—F13.9 ± 2.0835 ± 45 (503 ± 27)692 ± 27 (63 ± 2.5)1.71160.149.8
31Cl1.1 ± 0.137 ± 2.1 (22 ± 1.3)44.5 ± 1.3 (4.0 ± 0.12)1.71133.640.5
32Me1.7 ± 0.360 ± 0.53 (36 ± 0.32)240 ± 27 (23 ± 2.5)1.71035.3141
51Br1.7 ± 0.237.4 ± 5.2 (23 ± 3.1)10.6 ± 0.24 (0.96 ± 0.02)1.611226.24
55I1.3 ± 0.0136 ± 2.7 (22 ± 1.6)4.21 ± 0.30 (0.38 ± 0.03)1.61127.73.24
2aH101 ± 16541 ± 69 (271 ± 34)5700 ± 720 (518 ± 66)2.0115.3656.4
2bF21.0 ± 0.51200 ± 90 (741 ± 55)5060 ± 490 (460 ± 44)1.61157.1241
2cCl3.1 ± 0.65.14 ± 1.08 (3.1 ± 0.60)53 ± 3 (4.8 ± 0.26)1.7111.6617.1
2fMe10.2 ± 0.8270 ± 24 (160 ± 14)4250 ± 420 (390 ± 38)1.71126.5417
549Br1.7 ± 0.432.4 ± 3.5 (16.2 ± 1.7)84 ± 13.5 (20.6 ± 3.3)2.04.119.149.4
352I2.9 ± 0.252.4 ± 4.9 (32 ± 2.0)64.9 ± 1.97 (5.9 ± 0.18)1.61118.122.4
3aH670 ± 90>10000>10000—
3bF325 ± 87200 ± 810 (4340 ± 480)>100001.7—
3cCl25.0 ± 5444 ± 29 (222 ± 15)1450 ± 160 (356 ± 40)2.04.117.858.0
3fMe207 ± 212230 ± 380 (1120 ± 190)>100002.0—
3dBr15.7 ± 0.9272 ± 25 (136 ± 15)570 ± 80 (140 ± 20)2.04.117.336.3
3eI22.7 ± 0.9760 ± 49 (458 ± 30)66.3 ± 1.8 (6.0 ± 0.16)1.71133.52.92

LMA, D.D. and G.B.

LMA.GIF
CD Graph.GIF
Gross behavioral effects of various phenyltropane derivatives.gif

See also: [21] [22]

Closely related compounds have a varied aryl fragment, like naphthyl, or a varied tropane fragment like with exchanged heteroatom, trop-2-enes, quinuclidines, piperidines.

Related Research Articles

<span class="mw-page-title-main">WIN-35428</span> Chemical compound

(–)-2-β-Carbomethoxy-3-β-(4-fluorophenyl)tropane is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is structurally derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies. While the naphthalenedisulfonate salt is the most commonly used form in scientific research due to its high solubility in water, the free base and hydrochloride salts are known compounds and can also be produced. The tartrate is another salt form that is reported.

<span class="mw-page-title-main">(+)-CPCA</span> Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission.

<span class="mw-page-title-main">Troparil</span> Chemical compound

Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

<span class="mw-page-title-main">RTI-55</span> Chemical compound

RTI(-4229)-55, also called RTI-55 or iometopane, is a phenyltropane-based psychostimulant used in scientific research and in some medical applications. This drug was first cited in 1991. RTI-55 is a non-selective dopamine reuptake inhibitor derived from methylecgonidine. However, more selective analogs are derived by conversion to "pyrrolidinoamido" RTI-229, for instance. Due to the large bulbous nature of the weakly electron withdrawing iodo halogen atom, RTI-55 is the most strongly serotonergic of the simple para-substituted troparil based analogs. In rodents RTI-55 actually caused death at a dosage of 100 mg/kg, whereas RTI-51 and RTI-31 did not. Another notable observation is the strong propensity of RTI-55 to cause locomotor activity enhancements, although in an earlier study, RTI-51 was actually even stronger than RTI-55 in shifting baseline LMA. This observation serves to highlight the disparities that can arise between studies.

<span class="mw-page-title-main">Dichloropane</span> Chemical compound

Dichloropane ((−)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)tropane, RTI-111, O-401) is a stimulant of the phenyltropane class that acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) with IC50 values of 3.13, 0.79 and 18 nM, respectively. In animal studies, dichloropane had a slower onset and longer duration of action compared to cocaine.

<span class="mw-page-title-main">RTI-150</span> Chemical compound

RTI(-4229)-150, is a phenyltropane derivative which acts as a potent dopamine reuptake inhibitor and stimulant drug. It is around 5x more potent than cocaine, but is more selective for the dopamine transporter relative to the other monoamine transporters. RTI-150 has a fast onset of effects and short duration of action, and its abuse potential in animal studies is similar to that of cocaine itself; its main application in scientific research has been in studies investigating the influence of pharmacokinetics on the abuse potential of stimulant drugs, with the rapid entry of RTI-150 into the brain thought to be a key factor in producing its high propensity for development of dependence in animals. RTI-150 is not explicitly illegal anywhere in the world, but its similar structure and pharmacological activity to cocaine makes it possible that it would be considered a controlled substance analogue in countries such as the USA, Canada, Australia and New Zealand which have controlled substance analogue legislation.

<span class="mw-page-title-main">RTI-126</span> Pharmaceutical drug

RTI-126 is a phenyltropane derivative which acts as a potent monoamine reuptake inhibitor and stimulant drug, and has been sold as a designer drug. It is around 5 times more potent than cocaine at inhibiting monoamine reuptake in vitro, but is relatively unselective. It binds to all three monoamine transporters, although still with some selectivity for the dopamine transporter. RTI-126 has a fast onset of effects and short duration of action, and its pharmacological profile in animals is among the closest to cocaine itself out of all the drugs in the RTI series. Its main application in scientific research has been in studies investigating the influence of pharmacokinetics on the abuse potential of stimulant drugs, with its rapid entry into the brain thought to be a key factor in producing its high propensity for development of dependence in animals.

<span class="mw-page-title-main">RTI-336</span> Chemical compound

RTI(-4229)-336, is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine, however it produces relatively mild stimulant effects, with a slow onset and long duration of action. These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs, and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.

<span class="mw-page-title-main">RTI-113</span> Chemical compound

RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.

<span class="mw-page-title-main">RTI-112</span> Chemical compound

RTI(-4229)-112 is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113, which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor.

<span class="mw-page-title-main">RTI-177</span> Chemical compound

RTI(-4229)-177 is a synthetic stimulant drug from the phenyltropane family, which acts as a DRI with micromolar affinity for the SERT. RTI-177 has an unusually long duration of action of 20 hours or more, substantially longer than the related compound RTI-336 from which it differs in molecular structure only by the absence of a p-methyl group.

<span class="mw-page-title-main">RTI-31</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-4229-31) is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 x weaker than RTI-31, whereas RTI-51 was 2.6 x weaker than RTI-31.

<span class="mw-page-title-main">RTI-51</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4-bromophenyl)tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and RTI-55. Importantly it has a ratio of monoamine reuptake inhibition of D > S > N which is an unusual balance of effects not produced by other commonly used compounds. It has been used in its 76Br radiolabelled form to map the distribution of dopamine transporters in the brain.

<span class="mw-page-title-main">RTI-229</span> Chemical compound

RTI-229, also known as (–)-3β-(4-iodophenyl)tropane-2β-pyrrolidine carboxamide and RTI-4229-229, is a potent and long-lasting stimulant drug which was developed in the 1990s as part of a large group of related analogues from the phenyltropane family. With the combination of two potent dopamine transporter (DAT) binding motifs attached to the tropane ring, the p-iodophenyl group at the 3β-position and a pyrrolidine carboxamide at 2β, RTI-229 has extremely high selectivity for the dopamine transporter and is one of the most DAT-selective compounds in the RTI series.

<span class="mw-page-title-main">RTI-120</span> Chemical compound

(–)-2β-Carbophenoxy-3β-(p-tolyl)tropane (RTI-4229-120) is a phenyltropane derivative which acts as a reasonably selective dopamine reuptake inhibitor, along with weaker inhibition of noradrenaline and serotonin reuptake. It has a reasonably fast rate of occupancy of dopamine transporters in the brain, though slower than that of cocaine itself. RTI-120 has a short duration of action, along with other p-methyl substituted phenyltropanes such as RTI-150, RTI-171 and RTI-199, giving it a more similar pharmacological profile to cocaine compared to longer acting analogues like RTI-121 and RTI-177.

<span class="mw-page-title-main">RTI-83</span> Chemical compound

RTI-83 is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related neurotransmitter noradrenaline. With a binding affinity (Ki) of 55 nM at DAT and 28.4 nM at SERT but only 4030 nM at NET, RTI-83 has reasonable selectivity for DAT/SERT over NET

1-Methyl-3-propyl-4-(<i>p</i>-chlorophenyl)piperidine Chemical compound

1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine is a drug developed by a team led by Alan Kozikowski, which acts as a potent dopamine reuptake inhibitor, and was developed as a potential therapeutic agent for the treatment of cocaine addiction. As with related compounds such as nocaine, it is a structurally simplified derivative of related phenyltropane compounds. Its activity at the serotonin and noradrenaline transporters has not been published, though most related 4-phenylpiperidine derivatives are relatively selective for inhibiting dopamine reuptake over the other monoamine neurotransmitters. While several of its isomers are active, the (3S,4S)-enantiomer is by far the most potent. The rearranged structural isomer 2-[1-(4-chlorophenyl)butyl]piperidine is also a potent inhibitor of dopamine reuptake.

References

  1. ↑ "The methyl has to be at the other O, and trans" does not put the methyl group somewhere else in the molecule: the ester group is oriented more outward leading to a less congestion around the methyl group. A second benefit to this orientation is freeing the nitrogen atom to form hydrogen bonding or even accept a proton to form a better soluble positive charged ion.
  2. 1 2 Carroll, F. (2003). "2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy". Journal of Medicinal Chemistry . 46 (10): 1775–1794. doi:10.1021/jm030092d. PMID   12723940.
  3. 1 2 Runyon, S. P.; Carroll, F. I. (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Current Topics in Medicinal Chemistry. 6 (17): 1825–1843. doi:10.2174/156802606778249775. ISSN   1568-0266. PMID   17017960.
  4. ↑ USpatent 3813404,CLARKE R&DAUM S.,"TROPANE-2-CARBOXYLATES AND DERIVATIVES",published 1974-05-28
  5. ↑ Clarke, R. L.; Daum, S. J.; Gambino, A. J.; Aceto, M. D.; Pearl, J.; Levitt, M.; Cumiskey, W. R.; Bogado, E. F. (1973). "Compounds affecting the central nervous system. 4. 3 Beta-phenyltropane-2-carboxylic esters and analogs". Journal of Medicinal Chemistry. 16 (11): 1260–1267. doi:10.1021/jm00269a600. PMID   4747968.
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  11. ↑ Howell, L.; Carroll, F.; Votaw, J.; Goodman, M.; Kimmel, H. (2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics. 320 (2): 757–765. doi:10.1124/jpet.106.108324. PMID   17105829. S2CID   9205978.
  12. ↑ Howell, L. (2008). "Nonhuman primate neuroimaging and cocaine medication development". Experimental and Clinical Psychopharmacology . 16 (6): 446–457. doi:10.1037/a0014196. PMC   3228245 . PMID   19086766.
  13. ↑ Phillips, K.; Luk, A.; Soor, G.; Abraham, J.; Leong, S.; Butany, J. (2009). "Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options". American Journal of Cardiovascular Drugs. 9 (3): 177–196. doi:10.1007/bf03256574. PMID   19463023. S2CID   70385136.
  14. 1 2 Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal. 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC   2751440 . PMID   16584128.
  15. ↑ Daws, L. (2009). "Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics. 121 (1): 89–99. doi:10.1016/j.pharmthera.2008.10.004. PMC   2739988 . PMID   19022290.
  16. ↑ Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, et al. (November 2002). "Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder". Neuropsychopharmacology. 27 (5): 699–711. doi: 10.1016/S0893-133X(02)00346-9 . PMID   12431845.
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  18. ↑ Carroll, F.; Tyagi, S.; Blough, B.; Kuhar, M.; Navarro, H. (2005). "Synthesis and monoamine transporter binding properties of 3alpha-(substituted phenyl)nortropane-2beta-carboxylic acid methyl esters. Norepinephrine transporter selective compounds". Journal of Medicinal Chemistry . 48 (11): 3852–3857. doi:10.1021/jm058164j. PMID   15916437.
  19. ↑ Blough, B.; Abraham, P.; Lewin, A.; Kuhar, M.; Boja, J.; Carroll, F. (1996). "Synthesis and transporter binding properties of 3β-(4′-alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-2β-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of Medicinal Chemistry . 39 (20): 4027–4035. doi:10.1021/jm960409s. PMID   8831768.
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  22. ↑ Kimmel, H. .; O'Connor, J. .; Carroll, F. .; Howell, L. . (2007). "Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys". Pharmacology Biochemistry and Behavior. 86 (1): 45–54. doi:10.1016/j.pbb.2006.12.006. PMC   1850383 . PMID   17258302.
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