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Phenyltropane

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Template:Chembox new Phenyltropanes (PT's) are a large family of chemical compounds developed during research into the mechanism of action of certain kinds of drugs such as cocaine and other dopamine reuptake inhibitors. Phenyltropane compounds comprise a large family of related molecules, which in general act as inhibitors of the monoamine reuptake transporters. Different molecules in this family may be selective for a particular transporter such as the dopamine, noradrenaline or serotonin transporter, or may be non-selective and inhibit reuptake of all three monoamines. The following article briefly summarises the structure-activity relationships of these molecules and gives an outline of current research in the field.

Introduction

The 3-phenyltropane classes of MANRI’s (monoamine neuronal reuptake inhibitors) are both more potent in vitro and in vivo and more metabolically stable than cocaine. In addition, they have a slower onset of action and much longer duration of action. WIN-35,065-2 displays a much higher DAT selectivity than cocaine in vitro and is also more potent in vivo. Phenyltropanes are not normally local anesthetics because they lack the required ester link adjoining the tropane and phenyl rings. The most commonly used simple phenyltropane analogues in research are β-CFT, RTI-55 (β-CIT), and the p,m-Cl2 analogue Dichloropane. WIN-35065-2 (β-CPT) is also available; it is as potent as cocaine, although longer lasting due to increased metabolic stability. The MeO- from the 2β-CO2Me group can also be replaced to yield compounds with superior DAT affinity, that are even more metabolically stable, with the most potent analogues of β-CIT and dichloropane for instance being the carboisopropoxy and pyrrolidinylcarboxamide derivatives. The 2β-CONMe2 ester of β-CIT is a particularly promising target. Substitution on the nitrogen can also be successful in some instances, with the N-(γ-fluoropropyl) analogue of 2-carboisopropoxy-β-CIT being more potent than the simple N-methyl derivative. Fundamental research with tropane-based ligands has generated a host of excellent reviews and issued researchers with many promising molecules. (Satendra Singh)[1] (F. Ivy Carroll)[2][3][4] (Reith)[5][6]

(1R) 2-Methoxycarbonyl p-X 3-PT Diastereoisomers

Clarke et al. originally set out to separate the stimulant actions of cocaine from its toxicity and dependence liability.[7] These compounds are plain stimulants. Early studies demonstrated DAT in vitro binding can be strengthened via phenyl nucleus p-H replacement,[8] In a rat cocaine-discrimination tests, RTI-31 and RTI-32 were ~26 x and ~6 x more potent than cocaine, respectively.[9] This finding has led researchers to question if DAT binding alone is sufficient to account for PT's in vivo activity.[citation needed] Also some other vague factors here Although more recently, the aromatic catechol entity resulted in decreased potency,[10] p-OH was well tolerated in earlier work.[11] As the size of the p-moiety increases, the conditions required for inhibiting SERT become favorable and it is even possible to achieve a high level of selectivity for this transporter if the p-group becomes sufficiently inflated.[12][13] Most PT research has centered on the (1R,2S,3S) diastereoisomers because it is common knowledge that these possess higher activity than the weaker 2α,3β conformation.[14][15] Brasofensine[16][17] and tesofensine[18] both possess 2α,3β diastereochemistry though. So, it was also desirable to investigate other simple p-substituted diastereoisomer variations in conjunction with the (1R,2S,3S) conformation inorder to gain deeper insight into the dynamics of the tropane azabicycle. The other PT diastereoisomers are the 2α,3β– and 2β,3α conformers, although the latter is not immediately derived from alkylecgonidine and employs a forced synthetic pathway[19] The α,α isomers were completely braindead and have been omitted for clarity. The MAT IC50s, gross behaviour (GB), mice LMA data and cocaine-trained rat discrimination data of a variety of PT isomer variations is thus reported.[20]

MAT Binding

  • All the compounds have DAT IC50's exceeding SERT/NET affinity, but in the case of RTI-51/55 the SERT Ki value reaches <1nM.
  • DAT order of potency:
  • NET order of potency:
  • SERT order of potency:
Monoamine Transporter Binding Properties of 2-Carbomethoxy-3-p-Substituted-Phenyltropanes
Identification Marker DAT / NET / SERT IC50, nM (Ki, nM) IC50 ÷ Ki Uptake Ratio
Compound X [3H]CFT [3H]Nisoxetine [3H]Paroxetine NET SERT NE ÷ DA SER ÷ DA SER ÷ NA
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)>100001.991—164.5
  • DAT arrangement of diastereoisomer potency: (1R,2S,3S) > (1R,2S,3R) > (1R,2R,3S).
  • The p-Me 'obviously' possesses a greater propensity towards DAT selectivity than the halogens; although 2b serves to refute this oversimplification.

Locomotor Activity (LMA)

LMA studies has also been reported previously.[21][22] RTI-31, RTI-55 and 3c are all powerful LMA stimulants.   http://www.gerd-tentler.de/tools/phpgraphs/

Cocaine Discrimination (CD) and Gross Behaviour (GB)

For other CD studies see attached link.[23]

Percent of Rats Choosing the Cocaine Lever at the Dose (mg/kg) Specified and Gross Behavioral Effects
Compound .1 .17 .3 .56 1 1.7 3 5.6 10 17 30 ED50 1 mg/kg 10 mg/kg 100 mg/kg
Cocaine21325982972.44HAC,Sy,HA
WIN 35,065-2143688100.34Sy,HASy,HA,CcC,Sy,ST
WIN 35,42805786100.29 Sy(sl),HA(sl)Sy,HAC,Sy,ST
RTI-315044100.13Sy,HA,CcSySy,HL,ST
RTI-511450100.17Sy,HASy,CcSy,Cc
RTI-552225100.20Sy,HA,CcSy,HA(sl),CcD,Sy,HA(sl),HL
RTI-32025577186.31SySy
2a131001003.19Sy,HA(sl)Sy,HA,Cc
2b2938865.66Sy,HA(sl),CcSy,HA,Cc
2c252567671002.55HASy,Cc,Sn
2d131350882.98SnSy,HASy,Cc
2e0144344865.66HA(sl)
2f014294343751007.73HA(sl)Sy,HA,Cc
3a29671007.66C,Cc,Sn,HL,T,A
3b033571008.01Sy(sl)C,Sy,Ho,Cc,T
3c1388674.01SnD,C,Sy,Cc,T,A,ST
3d2517867.29Sy,Ho,PD,C,Sy,Ho,Cc,P,ST
3e0148013.51Sy(sl)D,C,Sy,HL,T,ST
3f1343717110013.51Sn(sl)C,Ho,Cc,HL,A
A, ataxia; C, convulsions; Cc, circling; D, death; EG, excessive grooming; FBP, flattened body posture; HA, hyperactivity; HL, hind limb splay; Ho, hypoactivity; MR, muscle relaxation; P, ptosis; (sl), slight or intermittent; Sn, stimulation; T, Straub tail; Sy, sterotypy; T, tremor.

Judging from the above tables/graphs, the (1R,2S,3S) compounds possess stronger MAT binding, greater potency as observed in the CD study, longer and duration of action (LMA graphs), as well as lower toxicity (observed gross effects). When you collate all of these factors together, the conclusion is reached that the (1R,2S,3S) diastereoisomers are more likely to be high value targets than any of the compounds catering a degree of α-diastereochemistry.

Methoxycarbonyl Alternatives

Un/saturated hydrocarbons

It should be noted that an ester group is not required for the activity of the tropane-containing DA reuptake blockers and compounds with a variety of other substitutions retain potent activity. (A.P. Kozikowski)[24][25][26][27][28] (Lifen Xu)[29][30]

2β-Ester-3β-phenyltropanes

These are more DAT selective than methyl esters, the i-Pr and Phenyl esters are the best. (F. Ivy Carroll)[31][32]

Amides

  • To obtain analogs with increased metabolic stability: CO2R → CO2H → C(O)Cl → C(O)NR2.
    • 3° amides were found to have higher DAT affinity than 1° and 2° amides.
    • RTI-31 –C(O)NMe2 amide has a DAT IC50 value of 1.28 nM and >>SER/NAR IC50 values is a potent super SDARI.
    • The –C(O)N(CH2)4 pyrrolidinocarboxamides are also similarly potent SDARI’s, although the –NEt2 amides are weaker.

An amide can undergo H-bonding, though weaker than an ester function deprending on its substitution pattern. The 2β-carboxamides, particularly with oxygen-bearing substituents were more potent within the same series of compounds.

The most potent and the most selective analogs was RTI-55-N-pyrrolidinocarboxamide;
and the morpholino amide of RTI-31 is called RTI-214, respectively.

Heterocycles

A set of 3-(4'-substituted phenyl)-2-heterocyclic tropanes was designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the corresponding WIN 35,065-2 analogs which possess a 2-carbomethoxy group. Several of the compounds showed high affinity and selectivity for the dopamine transporter (DAT) relative to the serotonin and norepinephrine transporters. From the structure-activity relationship study, the 3-(4'-chlorophenyl)-2-(3'-phenylisoxazol-5-yl)tropane (5d) emerged as the most potent and selective compound. The binding data for 2-heterocyclic tropanes were found to show a high correlation with molecular electrostatic potential (MEP) minima near one of the heteroatoms in the 2-substituents. In contrast, low correlations were found for other MEP minima near the 2-substituent as well as for calculated log P or substituent volume. These quantitative structure-activity relationship studies are consistent with an electrostatic contribution to the binding potency of these WIN 35,065-2 analogs at the DAT. (Kotian)[33]

Acyl

These arent so susceptible to hydrolysis as esters (Huw M. L. Davies).[34][35]

2β-Phenyl Group

These are not a piece of cake to make. (Sharadsrikar V. Kotturi)[36] (Songchun Jiang)[37]

2-Diarylmethoxymethyl

The authors decided to replace the benztropine pharmacophore and incorporate it into the PT sidechain position (Lifen Xu).[38]

Bivalent Analogs

"A series of aryltropane-based bivalent ligands was prepared and investigated for binding potency and for their ability to inhibit reuptake of human dopamine, serotonin and norepinephrine transporters. The bivalent ligand 4, comprised of linking an aryltropane by an octamethylene spacer showed high efficacy for the human dopamine transporter and had a discrimination ratio of 130."[39]

Desoxyn

These can be made in one step from their corresponding esters (desoxyn–O=COR). This RXN is technically a reduction: ROC=O → ROCH2.
Unfortunately, I am strictly forbidden to communicate the intensely classified experimental synthetic procedure for this chemical RXN.

8-Nitrogen Modification

Nortropanes

Transporter Binding Affinities for p-Alkylated Nor/phenyltropanes.
Identification Marker SERT / DAT / NET IC50, nM Uptake Ratio
Code X N [3H]Paroxetine [3H]WIN 35,428 [3H]Nisoxetine DA ÷ SER NA ÷ SER 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

Delocalized electrons around the p-area is very conducive towards improving MAT binding. Whilst N-demethylation dramatically improves NET/SERT binding, it has little effect on DAT. (Bruce E. Blough, Philip Abraham)[40] This effect is in good agreement Nor-Nocaine and may therefore be a good strategy to obtain nonselective compounds. In light of these observations it is somewhat strange that methylphenidate has such low SERT affinity.

Nortropanes are much more NET selective than the corresponding N-Me compounds. Transfixing tropane diastereoselectivity from 2β,3β– to 2β,3α– conformation 'buckles' the azabicyclic spatial outlay from the common chair to a flattened-boat, in an attempt to ↓ strain energy. p-Me,F,Cl (2β,3α)-N-PT's are relatively MAT nonselective with IC50s of 5–9nM (NET), 3-34nM (DAT) & 53–500nM (SERT). The (p-Me, m-F) dual-substituted N-PT has the sharpest NET selectivity and the greatest potency, it is 21-fold selective vs. 5-HTT and 55-fold vs. DAT. This NET selective tool may prove useful in probing NET importance w.r.t. psychostimulant abuse.[41]

N-Alkyl

http://jnm.snmjournals.org/cgi/content/abstract/47/3/520

N-Bridged

RTI-242

RTI Index

RTI-51,-31 and CFT

Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants. (2006)

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

RTI-76

2β(p-SCN-C6H4-O2C)-tropane-3β(p-chlorophenyl) is an irreversible DAT inhibitor.[42] "RTI-76 effectively removed the uptake component from recorded signals. Recent evidence suggests that release and uptake, key mechanisms determining brain extracellular levels of DA, are governed by presynaptic autoreceptors. The goal of this study was to investigate whether autoreceptors regulate both mechanisms concurrently. Extracellular DA in the caudate-putamen and nucleus accumbens, evoked by electrical stimulation of the medial forebrain bundle, was monitored in the anesthetized rat by real-time voltammetry."

RTI-336

 

Effects of DAT selective 3-phenyltropane analogs on LMA, drug discrimination, and cocaine self-administration after oral administration.

Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse.

Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys.

RTI-113

RTI-113, a 3-phenyltropane analog, produces long-lasting cocaine-like discriminative stimulus effects in rats and squirrel monkeys. (2002)

Relationship between self-administration and DAT occupancy determined by PET neuroimaging in rhesus monkeys. (2001)

Comparative Behavioral Pharmacology of Cocaine and the Selective Dopamine Uptake Inhibitor RTI-113 in the Squirrel Monkey. (2000)

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 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)

Disubstituted carboxymethyl phenyltropanes

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.[43][44][45] Not long afterwards, it was shown that they also possess <1nM SERT affinity.[46] This may be an important characteristic of these compounds since a number of reports suggest serotonin indirectly modulates nucleus accumbens dopamine release.[47][48]

The syntheses and MAT binding properties of several new dual substituted (1R,2S,3S) methoxycarbonyl p,m-PT's is thus reported.[49]

Identification Marker DAT / SERT / NET IC50, nM (Ki, nM) IC50 ÷ Ki Uptake Ratio
Compound p- m- [3H]WIN 35,428 [3H]Paroxetine [3H]Nisoxetine SER NE SER/DA NE/DA NA ÷ SER
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.

Mutant Rodents

DAT knock-out rats have elevated DA levels that accumulate in the synaptic cleft and consequently, display symptoms of overt hyperactivity etc.[50][51] The laboratory rat test-subjects still self-administered cocaine though; this prompted scientists into assuming cocaine-induced SERT inhibition must be at least partially capable of mitigating rewarding effects.[52][53]

It was determined by species scanning mutagenesis that residue F105 in TM2 of mouse DAT is important for ↑ affinity DAT binding. Cocaine Affinity Decreased by Mutations of Aromatic Residue Phenylalanine 105 in the Transmembrane Domain 2 of Dopamine Transporter </ref> Through 3-rounds of random mutagenesis at F105 a DAT mutant triple mutations.

Cocaine Affinity Decreased by Mutations of Aromatic Residue Phenylalanine 105 in the Transmembrane Domain 2 of Dopamine Transporter Xiaohong Wu1 and Howard H. Gu Vol. 63, Issue 3, 653-658, March 2003

Recent technological advancments created DAT knock-in mice where the DAT is still >50% functional, with the important exception that the cocaine recognition site was genetically modified so that DA re/uptake cant be blocked simply by consuming cocaine, although AMPH can still reliably induce euphoria.

Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter | June 13, 2006 | vol. 103 | no. 24 | 9333-9338. Rong Chen*, Michael R. Tilley*, Hua Wei*, Fuwen Zhou, Fu-Ming Zhou, San Ching, Ning Quan, Robert L. Stephens, Erik R. Hill*, Timothy Nottoli¶, Dawn D. Han*, and Howard H. Gu*,||,**

DAT CI mice do NOT self-administer cocaine. This recent study has served to effectively undermine the crackpot spin-out hypotheses and has revalidated the general tenets laid down by the DA hypothesis.

Cocaine still increases extracellular DA in the NAc of DAT-KO mice, probably through NET and/or SERT inhibition suggesting that the elevated extracellular DA might still underlie the mechanism of cocaine reward in mice lacking the DAT.

Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions. (2002)

Neuronal Targets

Dopamine

Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement (2007) J. Dalley

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys. (2007)

D2-Autoreceptors Chronically Enhance Dopamine Neuron Pacemaker Activity J Neurosci 2006 May 10; 26(19): 5240–5247.

Cooperative activation of D1- and D2-like DA receptors in the NAc shell is required for cocaine-seeking behavior in the rat (06) H.D. Schmidt

Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction (2006)

Changes in extracellular dopamine during cocaine self-administration in squirrel monkeys. Synapse, 56:129-134, 2005.

Dopamine and drug addiction: the nucleus accumbens shell connection. Gaetano Di Chiara, Valentina Bassareoa, Sandro Fenua, Maria Antonietta De Lucaa, Liliana Spinaa, Cristina Cadonia, Elio Acquasa, Ezio Carbonia, Valentina Valentinia and Daniele Leccaa 2004.

 

N-Epinephrine

Difference in magnitude of psychostimulant-induced extracellular norepinephrine in the ventral tegmental area contributes to discrepant prefrontal dopamine outflow Pan WH, Hsieh MC, Wu HH, Lin SK. Addict Biol. 2007 Mar;12(1):51-8.

Alpha-Noradrenergic Receptors Modulate the Development and Expression of Cocaine Sensitization (2006).

Role of the increased noradrenergic neurotransmission in drug self-administration. Wee S, Wang Z, He R, Zhou J, Kozikowski AP, Woolverton WL. 2005

Neurochemical interaction between dopaminergic and noradrenergic neurons in the medial prefrontal cortex Wynn Pan, Sze-Yuan Yang, Shi-Kwang Lin

Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Gainetdinov 2000

Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys (95 Spealman)

Serotonin

Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys. (2007)

Development of a Rationally Designed, Low Abuse Potential, Biogenic Amine Releaser That Suppresses Cocaine Self-Administration ('05)

Relationship between the Serotonergic Activity and Reinforcing Effects of a Series of Amphetamine Analogs (2005)

Role of serotonin in cocaine effects in mice with reduced dopamine transporter function. PNAS, January 6, 2004; 101(1): 372-377.

Serotonin1B Receptors in the Ventral Tegmental Area Modulate Cocaine-Induced Increases in Nucleus Accumbens Dopamine Levels 04

Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys. JPET 2002 300: 831-837.

The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Ronald B.P. Jobe 2005

σ–Receptors

σ Receptors: potential medications development target for anti-cocaine agents (03) Matsumoto

Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides R. Matsumoto, K. McCracken (2002).

Cholinergic

Pharmacological Characterization of Nicotine's Interaction with Cocaine and Cocaine Analogs J Pharmacol Exp Ther 1999 289: 1229-1236.

Ritz* Cocaine toxicity: concurrent influence of dopaminergic, muscarinic and sigma receptors in mediating cocaine-induced lethality '97

Ritz* Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors '97

Na+ Channels

In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. (2005)

On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys. (2000)

Ionotropic Glutamate Receptors

AMPA and NMDA Receptors in P2 Fractions of Cocaine and Cocaine–Prazosin-Treated Rats August 2006

Reduction of Corticostriatal Glutamatergic Fibers in Basic Fibroblast Growth Factor Deficient Mice is Associated with Hyperactivity and Enhanced Dopaminergic Transmission Dec 2006

Repeated cocaine administration differentially affects NMDA receptor subunit (NR1, NR2A-C) mRNAs in rat brain Mika Yamaguchi 1 2, Toshihito Suzuki 1 2 *, Shuzo Abe 2, Takafumi Hori 2, Hirofumi Kurita 2, Takashi Asada 2, Nobuo Okado 3, Heii Arai '02

Applications

Addiction

NEURAL MECHANISMS OF ADDICTION: The Role of Reward-Related Learning and Memory (July 2006)

Cocaine pharmacology and current pharmacotherapies for its abuse (October 2004)

Pharmacological treatment of cocaine dependence: a systematic review 02

Nature Reviews Drug Discovery 1, 710-726 (2002); doi:10.1038/nrd897 PHARMACOTHERAPY OF ADDICTIONS Mary Jeanne Kreek, K. Steven LaForge & Eduardo Butelman

ADHD

Dopamine genes and attention-deficit hyperactivity disorder: a review. J Psychiatry Neurosci. 2003 January; 28(1): 27–38.

Attention Deficit Hyperactivity Disorder: Pathophysiology and Design of New Treatments (Nov '04)

Parkinsons

Hypothesis: The role of dopaminergic transporters in selective vulnerability of cells in Parkinson's disease (Nov '97)

DAT: Basic science and human variation of a key molecule for dopaminergic function, locomotion, and parkinsonism (Sep '03)


Patents

Clarke Patent[54] Ivy Carroll Patents[55][56][57][58] Kozikowski Patents[59][60][61][62] Kuhar Patents[63][64][65][66][67][68] 5834484

References

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