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Nocaine was first reported in 1998 in the guise of a cocaine mimic.[1] Infact, phenylpiperidine derives from the same article in which phenyltropane was first published, but it was essentially impotent in tests conducted on mice. The (3R,4S) isomer of nocaine only manages to elicit weakly reinforcing effects, although it is several-fold less dangerous than cocaine. Thus, it is hypothesized that nocaine might be a good substitute type of agent with potential uses in treating cocaine addiction. Clearly, these compounds don't contain the necessary tropane 2C linker, required to deliver high intensity ambulatory counts, although they are still able to interact with MA transporters in an inhibitory fashion. In order to simply the situation in an a priori sense, it was chosen first to tune the focus into the DAT, since this is a critical recognition site, in the field of cocaine addiction (A. Kozikowski, et al. 1998). Given the similarity & innovation of these analogs, compared to PT based cocaine derivatives, steps were taken to explore their pharmacological activity (W. Woolverton, et al. 2002),[2] (A. Kozikowski, et al. 2003).[3]

Nocaine: Basic Pharmacology

Like cocaine, SS and 3R,4S bind to the DAT and inhibit DA uptake, stimulate LMA in rodents and completely substitute for cocaine in 2D tests. Pretreatment with SS or 3R,4S enhances the cocaine discriminative stimulus in rats. However, the LMA effects of the piperidine based compounds are much less than those induced by cocaine. Pretreating mice with SS or 3R,4S does not increase cocaine induced convulsions in mice. Furthermore, pretreating mice with 3R,4S actually attenuated cocaine-induced locomotor stimulation. With regard to reinforcing effects, SS is similar to cocaine as revealed by their nearly identical inverted U-shaped dose-response curves in fixed-ratio self-administration tests in rats. 3R,4S, however, has a flat dose-response curve in FR SA tests. Similarly, SS and cocaine had nearly identical break points in a PR SA test, whereas 3R,4S has a lower break point than either of these two drugs.

Monoamine Reuptake Activity
Compound [3H]NE nM [3H]5-HT nM [3H]DA nM 5-HT/NE DA/5-HT DA/NE
Cocaine119 ± 38177 ± 13275 ± 241.4871.5542.311
SS98 ± 7390 ± 2767 ± 243.980.1718.6837
(3R,4S)90 ± 55900 ± 400276 ± 3365.56.04683.067


The generally lower efficacy of 3R,4S in locomotor and methamphetamine discrimination tests could result from the differential selectivity of the two isomers for the DAT relative to the SERT. That is, if serotonin receptor activation is requisite for maximal efficacy, the difference SERT affinity between SS and 3R,4S might play a contributory role in accounting for the differences in the observed pharmacology. Catecholamine selective drugs, like TMP (methylphenidate), are reported to possess decent abuse potential though, so it is not easy to gauge why the trans analog, does not entice a strong SA propensity. In the specific case of Indatraline, the trans layout is actually desirable.

A possible explanation might be 3R,4S nocaine binds to the DAT in a different kind of fashion to SS and cocaine. If this is the case, it shouldn't be viewed as surprising that it is less reinforcing and possibly even aversive (S. Lomenzo, et al. 2005).[4]

Some sort of cholinergic effect might also be aversive. For example, muscarinic activity of benztropine analogs is known to limit their reinforcing potential (M. Zou, et al. 2006).[5] Ion-channel activity is another factor that can be used to explain certain differences in pharmacology.

Another possible explanation may lie in the fact that these compounds lack activity at the σ-receptors (R. Matsumoto, et al.).[6][7][8][9][10][11] See also, (Ping and Teruo, rev 2003).[12] Sigma receptor activity is characteristic of cocaine, methamphetamine and phencyclidine. Administering sigma-receptor antagonists can reverse cocaine-induced lethality, and also suppresses locomotor activity. Since the piperidine based ligands do not have sigma receptor activity, it can be hypothesized that this may be one of the possible reasons in accounting for their lack of locomotor activity, lessened probability to induce convulsions at high doses, etc.

Also, GABA activity is another neural target, cf. benzodiazapine and baclofen.

In summary, 3R,4S has lower potency and efficacy than than cocaine in increasing LMA in rodents. 3R,4S only manages to produce partial methamphetamine-like discriminative stimulus effects, although it is fully cocaine-like in cocaine-trained animals. 3R,4S has lower reinforcing potential than cocaine as assessed by fixed and progressive ratio IV self-administration tests in rats, with its reinforcing effects confirmed by rhesus monkeys. Furthermore, 3R,4S dose dependently antagonizes cocaine-induced LMA and potentiates the discriminative stimulus effects of a low dose of cocaine. 3R,4S, unlike cocaine, does not enhance cocaine-induced convulsions.

Clearly, SS is much better than (3R,4S), although maybe not as desirable as cocaine.

Triple Monoamine QSAR

Based upon the results reported in the tropane series, it became desirable to modify the aryl-arecoline nucleus, in ways that were predicted to improve SERT affinity, and also maintain/strengthen DAT/NET binding (A. Tamiz, et al. 2000).[13] A series of Nocaine analogs were tested for their ability to inhibit the high affinity synaptic re/uptake of tritium radiolabelled biogenic monoamines, at DA/NE/5HT neurotransporters. The uptake data and selectivity profiles of these compounds are listed in the table. The 4-(β-naphthyl) 3-CO2Me compound is related to RTI-318. The p-allyl compound is a piperidine based mimic of RTI-301. It is depicted as the terminal alkene, although it should be emphasized that the olefin will internalize upon exposure to light. Then there are two isomers, each with a different code.

Triple MAT Activity of the Piperidine Based Cocaine Mimics
Identification Marker SERT / DAT / NET IC50, nM (K, nM) IC50 ÷ Ki IC50 Ratio
Config X N [3H]Serotonin [3H]Dopamine [3H]Noradrenaline 5-HT DA NE DA/5HT NE/5HT NE/DA
SSp-VinylMe155 ± 3.9 (138 ± 3.5)144 ± 20 (131 ± 18)204 ± 5.6 (175 ± 4.8)1.1231.0991.1660.94931.2681.336
SSp-EthylMe275 ± 39 (255 ± 37)>1800 (>1700)>1300 (>1100)1.0781.0591.182>6.667>4.3140.6471
SSp-AllylMe334 ± 48 (309 ± 44)>1000 (964 ± 100)>1200 (>1000)1.081>1.0371.23.120>3.2361.037
SSp-EthynylMe189 ± 37 (175 ± 34)213 ± 30 (187 ± 26)399 ± 12 (364 ± 9.2)1.0801.1391.0961.0692.0801.947
SSp-PhenylMe67 ± 4.5 (62 ± 4.1)184 ± 30 (173 ± 26)239 ± 42 (203 ± 36)1.0811.0641.1772.7903.2741.173
SSβ-NaphthylMe8.2 ± 0.3 (7.6 ± 0.2)23 ± 1.0 (21 ± 0.9)n.d. (34 ± 0.8)1.0791.0952.7634.4741.619
3R,4Sβ-NaphthylMe46 ± 4.4 (42 ± 4.0)>1000 (947 ± 135)n.d. (241 ± 1.7)1.095>1.05622.555.7380.2545
RRβ-NaphthylMe209 ± 17 (192 ± 16)94 ± 9.6 (87 ± 8.9)n.d. (27 ± 1.6)1.0891.0800.45310.14060.3103
3S,4Rβ-NaphthylMe13 ± 0.7 (12 ± 0.7)293 ± 6.4 (271 ± 5.9)n.d. (38 ± 4.0)1.083 1.08122.583.1670.140
3S,4Rβ-NaphthylH2Cl3.9 ± 0.5 (3.5 ± 0.5)97 ± 8.6 (90 ± 8.0)34 ± 2.5 (30 ± 2.3)1.1141.0781.13325.718.5710.3333
SS/RRα-NaphthylMe113 ± 4.3 (101 ± 3.8)326 ± 1.2 (304 ± 1.1)337 ± 37 (281 ± 30)1.119 1.0721.1993.0102.7820.9243
All data are mean values ± range or SEM of 2–5 separate experiments each conducted with 6 drug concentrations in triplicate.

The vinyl compound was picked to represent this series of compounds in LMA studies. Both cocaine and the vinyl compound stimulated LMA. However, cocaine is ~2.5 x more potent in increasing the distance traveled. In contrast, the vinyl compound is about ~2.4 x more potent in enhancing stereotypic movements. Both cocaine and vinyl-Nocaine had a similar time-course on locomotor effects, which was ~2 h.

It is important to point out, in the case of the β-naphthyl isomers, although SERT activity is tolerated in both cis and trans cases, DAT activity is better tolerated for the cis isomers, meaning that these can be honored, whereas the trans isomers should be discarded. Enantiomeric separations may or may not be desirable, dependent on the exact identity of the aromatic entity.

Nocaine: Ester and Amine Modifications

A series of novel N- and 3α-modified Nocaine analogs were synthesized and tested for their SNDRI activity and behavioral properties in mice (Petukhov, et al. 2002).[14]

The rational design of ligands with a predetermined potency at and selectivivity for DA/NE/5HT transporters is hindered by the lack of knowledge about the 3D structure (U. Gether, et al. 2001),[15] (N. Chen, et al. 2000).[16]

"In cases where the 3D structure of the binding site in a target protein is not well defined, as is the case for the MATs, one can perform ligand-based design to develop a pharmacophore. That is, by studying the conformational properties of a series of pharmacologically similar compounds, one can form hypotheses regarding the pharmacophore" (M. Froimowitz, et al. 2007).[17]

In other words, the logical design of novel drugs is made possible, using ab initio principles, or at least by semi-empirical methods.

(+)-CPCA N-demethyl and Ester Modified MAT QSAR
Identification Marker Ki (nM) Uptake Ratio
Tag R N [3H]NE [3H]DA [3H]5-HT DA ÷ NE 5-HT ÷ DA 5-HT ÷ NE
1aCO2MeMe252 ± 43233 ± 628490 ± 1430.924636.4433.69
1bH7.9 ± 3.0279 ± 98434 ± 5035.321.55654.94
2aCH2OHMe198 ± 53497 ± 581550 ± 3602.5103.1197.828
2bH69 ± 6836 ± 35239 ± 2812.12.28593.464
3aOxadiazoleMe256 ± 17187 ± 35960 ± 80.730531.8723.28
3bH34 ± 6189 ± 24373 ± 45.5591.97410.97

N-demethylation led to positive enhancements in strength at the NET and the SERT in vitro. However, convulsions were witnessed at the highest dose tested, which could undermine the safety expectancy of these compounds. Interestingly, the demethyl ester also had increased duration span, which was unexpected, although it functioned as an unreliable behavioral enhancer, in contrast to the other compounds.

The alcohol is a better SERT blocker, than either the ester or the oxadiazole, which seem to discriminate against this receptor.

Both the alcohol and the oxadiazole had increased duration relative to the ester, although the alcohol had a delayed onset of action. This is accounted for on the basis of its increased polarity, meaning that it is likely to take longer to pass the BBB.

3α-Substituted Nocaine Ligand Design

In an earlier study, it was found that 3α-amido and bulky 3α-oxadiazoyl nocaine ligands, which possess greater stability relative to the ester FG, and are therefore more attractive as potential therapies, are inactive (P. Petukhov, et al. 2001).[18] This result led to the hypothesis that the binding site of the DAT and NET in close proximity to the 3α-position of the piperidine ring is compact and cannot accomodate bulky, sterically occluded substituents, like the 3-substituted 1,2,4-oxadiazolyl groups. Supplied with this information, it was reasoned that introduction of a methylene spacer would confer improved MAT binding affinity upon the resultant molecules (P. Petukhov, et al. 2004).[19]

MAT Activity of the Ligands
Identification Marker Ki (nM) Uptake Ratio Physicochemical
Tag R [3H]DA [3H]5-HT [3H]NE 5-HT/DA NE/DA NE/5-HT CLogP MW
1aCOOMe2338490252361.1.0303.22268
1gCONMe22140189005698.8.27.0302.77281
2bCH2OAc5999012351.5.39.262.98282
2dCH2OCH2CH=CH260231203.9.33.0873.38280
2iCH2COOEt791911012.41.3.533.34296
2nCH2CONMe2161994461252.9.0232.80295
2pHeterocycle443252.731.21.64.72412
3aCH2CH2COOMe68255313.8.46.123.34296
3btrans CH=CHCO2Me535012729.55.1.543.42294
4aCH2CH2CH3202286.511.33.0294.91252
4bCH2CH2CH2OH16281056417535.203.09268
Heterocycle = 3-[(1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]

One of the possible reasons that the C2–C3 compounds are more active than the C1 compounds is that the polar group present in the more flexible 3α-appendage of the C2–C3 ligands is able to avoid unfavorable interactions with the binding site in close proximity to the piperidine ring. For the same reason the appendage in the C2–C3 series may more closely, but not precisely, mimic the binding mode of the more active SS based ligands, and possibly even transfer over to tropane based compounds.

To better understand the difference between the C1 and the C2–C3 series, the compounds were energy minimized and flexibly superimposed on WIN35428. Additionally, the conformation of the 3α-substituents were adjusted to maintain the closest possible overlap with the 2β-substituent of WIN35428, which helps avoid the SEA discussed earlier.

The resulting overlay shows that only the C2–C3 ligands are able to adopt a conformation in which the polar group of the 3α-substituent occupies the position proximal to that of the 2β-polar group in WIN35428.

DAT Arylpiperidine CoMFA Study

In this study a host of (3R,4S) Nocaine ligands were used as a test bed to do molecular modeling, using in vitro DAT binding data from earlier work (H. Yuan, et al. 2004).[20] Two highly predictive and statistically significant CoMFA models were constructed.

Nocaine: Sulfur Appendage

The carboxymethyl locus of (d)-(3R,4S) Nocaine was used to generate a cluster of new side-chains, each imbuing various different shapes and sizes etcetera. One such example is a rigorously functionalized thioalkyl chain. The eugeroic, "wakefulness promoting agent" modafinil, was used as a punitative lead, to fuel these compounds discovery, although it turns out that the SAR of the pharmacophoric elements are, infact, only fleetingly related to one another (J. Zhou, et al. 2004).[21] The NRI selective molecules discovered in this study were employed as brain imaging agents, to unravel details about the NE transporter (J. Musachio, et al, 2006).[22] The other isomers of these sulfur-appendage "modafinil hybrids" were prepared, although it appears that it was no mistake that the (3R,4S) isomers yielded the most potent MAT inhibitor activity, in the preliminary study (R. He, et al. 2005).[23]

MAT Binding Properties of "Modafinil Hybrids"
Identification Marker NET / DAT / SERT Ki (nM) Ki Ratio
R X Y [3H]Norepinephrine [3H]Dopamine [3H]Serotonin DA/NE SER/DA SER/NA
MeEsterOMe25 ± 680 ± 23208 ± 473.22.68.32
H.56 ± .0951 ± 1613 ± 391.07.254923.21
MeAmideHNH39 ± 5159 ± 19557 ± 1504.0773.50314.28
H10 ± .1114 ± 32170 ± 611.41.49117
MeHNOH15 ± 285 ± 19227 ± 75.6672.67115.13
HNMe25 ± 213 ± 3110 ± 45.528.4624.4
MeNMe27 ± 7116 ± 4688 ± 224.296.75863.259
isopropyl-NH.8 ± .11.0 ± .21.1 ± .41.251.11.375
pyrrolidino.68 ± .2583 ± 14.5 ± .8122.1.054226.618
H2OH.94 ± .2716 ± 5158 ± 517.029.875168.1
OMe6 ± 250 ± 15191 ± 578.3333.8231.83
OAc3.6 ± 1.535 ± 1157 ± 189.7221.62315.83
OBz4.5 ± 1.268 ± 226.7 ± 1.515.11.098531.489

NRIs are important probes, but they are not thought to function as robust or powerful reinforcers (S. Wee, et al. 2006).[24]

However, more focus has been tuned in to the ligand that has low nanomolar affinity at all three monoamine transporters, the first broadcasted piperidine compound developed to show such potent "triple reuptake inhibition".

It is also of note, that upon treatment of the ligands with H2O2 (hydrogen peroxide), the sulfur atom is oxidized. The resultant molecules then lose their ability to interact, with MA transporters, in an inhibitory fashion. Since all of these were less active than the unoxidized ligands, they were deliberately omitted from the above table. Thus, oxidation can be thought to sabbotage the biological activity of these ligands.

3D-QSAR Methods

http://dx.doi.org/10.1016/j.bmc.2006.09.070

External links

Pat Retrieval

[25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]

References

  1. [1]Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton. Alan P. Kozikowski, Gian Luca Araldi, John Boja, William M. Meil, Kenneth M. Johnson, Judith L. Flippen-Anderson, Clifford George, and Eddine Saiah. J. Med. Chem. 1998; 41(11) pp 1962 - 1969
  2. [2]Reinforcing Strength of a Novel Dopamine Transporter Ligand: Pharmacodynamic and Pharmacokinetic Mechanisms. W. L. Woolverton, R. Ranaldi, Z. Wang, G. A. Ordway, I. A. Paul, P. Petukhov, and A. Kozikowski. J. Pharmacol. Exp. Ther. 2002 303: 211-217.
  3. [3]Mixed Cocaine Agonist/Antagonist Properties of (+)-Methyl 4-(4-Chlorophenyl)-1-methylpiperidine-3-carboxylate, a Piperidine-Based Analog of Cocaine. Alan P. Kozikowski, Kenneth M. Johnson, Olivier Deschaux, Bidhan C. Bandyopadhyay, Gian Luca Araldi, Gilberto Carmona, Patrik Munzar, Miles P. Smith, Robert L. Balster, Patrick M. Beardsley and Srihari R. Tella. J. Pharmacol. Exp. Ther. 2003 305: 143-150.
  4. [4]Synthesis and Biological Evaluation of Meperidine Analogues at Monoamine Transporters. Lomenzo, S. A.; Rhoden, J. B.; Izenwasser, S.; Wade, D.; Kopajtic, T.; Katz, J. L.; Trudell, M. L. J. Med. Chem. 2005; 48(5); 1336-1343.
  5. [5]Structure-Activity Relationship Studies on a Novel Series of (S)-2-Substituted 3-[Bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane Analogues for in Vivo Investigation. Zou, M.-F.; Cao, J.; Kopajtic, T.; Desai, R. I.; Katz, J. L.; Newman, A. H. J. Med. Chem. 2006; 49(21); 6391-6399.
  6. [6]Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to σ-receptors rather than dopamine transporters. Rae R. Matsumoto, Kizzy L. Hewett, Buddy Pouw, Wayne D. Bowen, Stephen M. Husbands, Jian Jing Cao and Amy Hauck Newman. Neuropharmacology, Volume 41, Issue 7, December 2001, Pages 878-886.
  7. [7]Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting σ1 receptors produce anti-cocaine effects in mice. Rae R. Matsumoto, Kari A. McCracken, Michele J. Friedman, Buddy Pouw, Brian R. De Costa and Wayne D. Bowen. European Journal of Pharmacology, Volume 419, Issues 2-3, 11 May 2001, Pages 163-174.
  8. [8]Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides. Rae R. Matsumoto, Kari A. McCracken, Buddy Pouw, Ying Zhang and Wayne D. Bowen. Neuropharmacology, Volume 42, Issue 8, June 2002, Pages 1043-1055.
  9. [9]σ Receptors: potential medications development target for anti-cocaine agents. Rae R. Matsumoto, Yun Liu, Megan Lerner, Eric W. Howard and Daniel J. Brackett. European Journal of Pharmacology, Volume 469, Issues 1-3, 23 May 2003, Pages 1-12.
  10. [10]Involvement of sigma (σ) receptors in the acute actions of methamphetamine: Receptor binding and behavioral studies. Emily C. Nguyen, Kari A. McCracken, Yun Liu, Buddy Pouw and Rae R. Matsumoto. Neuropharmacology, Volume 49, Issue 5, October 2005, Pages 638-645
  11. [11]Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice.
  12. [12]Understanding the Molecular Mechanism of Sigma-1 Receptors: Towards A Hypothesis that Sigma-1 Receptors are Intracellular Amplifiers for Signal Transduction. pp. 2073-2080(8) Authors: Su Tsung-Ping; Hayashi Teruo
  13. [13]Further SAR Studies of Piperidine-Based Analogues of Cocaine. 2. Potent Dopamine and Serotonin Reuptake Inhibitors. Amir P. Tamiz, Jianrong Zhang, Judith L. Flippen-Anderson, Mei Zhang, Kenneth M. Johnson, Olivier Deschaux, Srihari Tella, and Alan P. Kozikowski. J. Med. Chem. 2000; 43(6) pp 1215 - 1222
  14. [14]SAR Studies of Piperidine-Based Analogues of Cocaine. 4. Effect of N-Modification and Ester Replacement. Pavel A. Petukhov, Jianrong Zhang, Alan P. Kozikowski, Cheng Z. Wang, Yan Ping Ye, Kenneth M. Johnson, and Srihari R. Tella J. Med. Chem. 2002; 45(15) pp 3161 - 3170.
  15. [15]Delineating structure-function relationships in the dopamine transporter from natural and engineered Zn2+ binding sites Life Sciences, Volume 68, Issues 19-20, 6 April 2001, Pages 2187-2198 Ulrik Gether, Lene Norregaard and Claus Juul Loland
  16. [16]Structure and function of the dopamine transporter. European Journal of Pharmacology, Volume 405, Issues 1-3, 29 September 2000, Pages 329-339. Nianhang Chen and Maarten E. A. Reith
  17. [17]Slow-Onset, Long-Duration, Alkyl Analogues of Methylphenidate with Enhanced Selectivity for the Dopamine Transporter. Mark Froimowitz, Yonghong Gu, Les A. Dakin, Pamela M. Nagafuji, Charles J. Kelley, Damon Parrish, Jeffrey R. Deschamps, and Aaron Janowsky. J. Med. Chem. 2007; 50(2) pp 219 - 232.
  18. [18]SAR Studies of Piperidine-Based Analogues of Cocaine. Part 3: Oxadiazoles. Pavel A. Petukhov, Mei Zhang, Kenneth J. Johnson, Srihari R. Tella and Alan P. Kozikowski. Bioorganic & Medicinal Chemistry Letters, Volume 11, Issue 16, 20 August 2001, Pages 2079-2083
  19. [19]Synthesis, Molecular Modeling, and Biological Studies of Novel Piperidine-Based Analogues of Cocaine: Evidence of Unfavorable Interactions Proximal to the 3-Position of the Piperidine Ring. Pavel A. Petukhov, Jianrong Zhang, Cheng Z. Wang, Yan Ping Ye, Kenneth M. Johnson, and Alan P. Kozikowski. J. Med. Chem. 2004; 47(12) pp 3009 - 3018.
  20. [20]CoMFA Study of Piperidine Analogues of Cocaine at the Dopamine Transporter: Exploring the Binding Mode of the 3-Substituent of the Piperidine Ring Using Pharmacophore-Based Flexible Alignment. Hongbin Yuan, Alan P. Kozikowski, and Pavel A. Petukhov. J. Med. Chem. 2004; 47(25) pp 6137 - 6143.
  21. [21]Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization. Jia Zhou, Rong He, Kenneth M. Johnson, Yanping Ye, and Alan P. Kozikowski J. Med. Chem. 2004; 47(24) pp 5821 - 5824
  22. [22]Development of new brain imaging agents based upon nocaine–modafinil hybrid monoamine transporter inhibitors. John L. Musachio, Jinsoo Hong, Masanori Ichise, Nicholas Seneca, Amira K. Brown, Jeih-San Liow, Christer Halldin, Robert B. Innis, Victor W. Pike, Rong He, Jia Zhou and Alan P. Kozikowski, Bioorganic & Medicinal Chemistry Letters, Volume 16, Issue 12, 15 June 2006, Pages 3101-3104
  23. [23]Further Structure-Activity Relationship Studies of Piperidine-Based Monoamine Transporter Inhibitors: Effects of Piperidine Ring Stereochemistry on Potency. Identification of Norepinephrine Transporter Selective Ligands and Broad-Spectrum Transporter Inhibitors. He, R.; Kurome, T.; Giberson, K. M.; Johnson, K. M.; Kozikowski, A. P. J. Med. Chem. 2005; 48(25); 7970-7979.
  24. [24]Role of the increased noradrenergic neurotransmission in drug self-administration. Sunmee Wee, Zhixia Wang, Rong He, Jia Zhou, Alan P. Kozikowski and William L. Woolverton. Drug and Alcohol Dependence, Volume 82, Issue 2, 28 April 2006, Pages 151-157
  25. DE1110159 Publication date: 1961-07-06 Improvements in or relating to Amino-Norcamphane compounds
  26. United States Patent 3,813,404 Issue Date: May 28, 1974
  27. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6180648, 2001.
  28. United States Patent 6,376,673 Moldt, et al. April 23, 2002 Piperidine derivatives as neurotransmitter re-uptake inhibitors
  29. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6472422, 2002.
  30. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6806281, 2004.
  31. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, WO9845263, 1998
  32. Kozikowski; Alan P.; Araldi; Gian Luca; Tamiz; Amir P., WO0020390, 2000.
  33. WO2004039778 Date: 2004-05-13 Inventor: WAETJEN FRANK (DK) Applicant: NEUROSEARCH AS (DK); WAETJEN FRANK (DK)
  34. KOZIKOWSKI ALAN P (US); ZHOU JIA (US), WO2005041875, 2005.
  35. KOZIKOWSKI ALAN P (US); ZHOU JIA (US); EP1680113, 2006-07-19; UNIV GEORGETOWN (US)

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