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Aminorex
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<h2 id="pharmacology">Pharmacology</h2> <h3>Pharmacodynamics</h3> <p>Aminorex is a <a href="/facts/Serotonin%25E2%2580%2593norepinephrine%25E2%2580%2593dopamine_releasing_agent/F83X4jjy">serotonin–norepinephrine–dopamine releasing agent</a> (SNDRA).<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> Its <a href="/facts/Half-maximal_effective_concentration/x7oD7ITx">EC50</a>Tooltip half-maximal effective concentration values for <a href="/facts/Monoamine_releasing_agent/JwSvmyR8">induction of monoamine release</a> are 26.4 nM for <a href="/facts/Norepinephrine/AjTIC9ox">norepinephrine</a>, 49.4 nM for <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a>, and 193 nM for <a href="/facts/Serotonin/EzY58q4a">serotonin</a>.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> In addition to its monoamine-releasing activity, aminorex is a weak <a href="/facts/Agonist/nz8U5NNp">agonist</a> of the <a href="/facts/Serotonin/EzY58q4a">serotonin</a> <a href="/facts/5-HT2_receptor/83TWw6EC">5-HT2 receptors</a>, including of the serotonin <a href="/facts/5-HT2A_receptor/YfTglQKQ">5-HT2A</a>, <a href="/facts/5-HT2B_receptor/Sy104fUR">5-HT2B</a>, and <a href="/facts/5-HT2C_receptor/RuyLstWf">5-HT2C receptors</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Its EC50 values for activation of these receptors are 4,365 nM for 5-HT2A, 870 nM for 5-HT2B, and 525 nM for 5-HT2C.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <a href="/facts/Monoamine_releasing_agent/JwSvmyR8">Monoamine release</a> of aminorex and related agents (<a href="/facts/Half_maximal_effective_concentration/x7oD7ITx">EC50</a>Tooltip Half maximal effective concentration, nM)<table><tbody><tr><th>Compound</th><th><a href="/facts/Norepinephrine/AjTIC9ox">NE</a>Tooltip Norepinephrine</th><th><a href="/facts/Dopamine/5gNy8Xkd">DA</a>Tooltip Dopamine</th><th><a href="/facts/Serotonin/EzY58q4a">5-HT</a>Tooltip Serotonin</th><th>Ref</th></tr><tr><td><a href="/facts/Phenethylamine/XyjysSul">Phenethylamine</a></td><td>10.9</td><td>39.5</td><td>>10,000</td><td><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></td></tr><tr><td><a href="/facts/Dextroamphetamine/SoVP3mKN">Dextroamphetamine</a></td><td>6.6–10.2</td><td>5.8–24.8</td><td>698–1,765</td><td><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a></td></tr><tr><td><a href="/facts/Dextromethamphetamine/vS1jloMe">Dextromethamphetamine</a></td><td>12.3–14.3</td><td>8.5–40.4</td><td>736–1,292</td><td><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a></td></tr><tr><td>Aminorex</td><td>15.1–26.4</td><td>9.1–49.4</td><td>193–414</td><td><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></td></tr><tr><td><a href="/facts/4-Methylaminorex/YmtPUVNR"><i>cis</i>-4-MAR</a></td><td>4.8</td><td>1.7</td><td>53.2</td><td><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></td></tr><tr><td><a href="/facts/4%2c4%2527-Dimethylaminorex/JUtrhoAb"><i>cis</i>-4,4'-DMAR</a></td><td>11.8–31.6</td><td>8.6–24.4</td><td>17.7–59.9</td><td><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a></td></tr><tr><td><a href="/facts/4%2c4%2527-Dimethylaminorex/JUtrhoAb"><i>trans</i>-4,4'-DMAR</a></td><td>31.6</td><td>24.4</td><td>59.9</td><td><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a><a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a></td></tr><tr><td><a href="/facts/3%2527%2c4%2527-Methylenedioxy-4-methylaminorex/9yIV2DBV"><i>cis</i>-MDMAR</a></td><td>14.8</td><td>10.2</td><td>43.9</td><td><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a></td></tr><tr><td><a href="/facts/3%2527%2c4%2527-Methylenedioxy-4-methylaminorex/9yIV2DBV"><i>trans</i>-MDMAR</a></td><td>38.9</td><td>36.2</td><td>73.4</td><td><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a></td></tr><tr><td colspan="5">Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The <a href="/facts/Bioassay/hRM3LIJn">assays</a> were done in rat brain <a href="/facts/Synaptosome/VTwyaNB1">synaptosomes</a> and human <a href="/facts/Potency_(pharmacology)/D38FDyPh">potencies</a> may be different. See also <a href="/facts/Monoamine_releasing_agent/JwSvmyR8">Monoamine releasing agent § Activity profiles</a> for a larger table with more compounds. Refs: <a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a><a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a></td></tr></tbody></table> <p>Activation of serotonin 5-HT2B receptors by aminorex, either directly via agonism or indirectly via serotonin release, has been implicated in the development of <a href="/facts/Pulmonary_arterial_hypertension/4848aBJl">pulmonary arterial hypertension</a> and <a href="/facts/Cardiac_valvulopathy/V7lraqpM">cardiac valvulopathy</a> with the drug.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a><a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a><a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> However, its EC50 for serotonin 5-HT2B receptor activation is 33-fold higher than its EC50 value for induction of norepinephrine release and is almost 50-fold less <a href="/facts/Potency_(pharmacology)/D38FDyPh">potent</a> than the serotonin 5-HT2B receptor agonism of <a href="/facts/Norfenfluramine/kk4YBId6">dexnorfenfluramine</a>.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> This seems to call into question the role of direct agonism of the serotonin 5-HT2B receptor in the <a href="/facts/Toxicity/qa96rs60">toxicity</a> of aminorex.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> Along similar lines, <a href="/facts/Chlorphentermine/e3P8lhBT">chlorphentermine</a>, a related drug that has also been associated with such adverse effects, shows negligible direct serotonin 5-HT2B receptor agonistic activity.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> However, it is possible that <a href="/facts/Metabolite/nAyywVtA">metabolites</a> of aminorex and chlorphentermine might be more potent in this action.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> </p><p>Aminorex does not appear to have been assessed at the <a href="/facts/Trace_amine-associated_receptor_1/Xf3Qpjtw">trace amine-associated receptor 1</a> (TAAR1).<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a><a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> However, several <a href="/facts/Chemical_derivative/JYcbLkbm">derivatives</a> of aminorex, such as <a href="/facts/4-methylaminorex/YmtPUVNR">4-methylaminorex</a> (4-MAR) and <a href="/facts/4%2c4%2527-dimethylaminorex/JUtrhoAb">4,4'-dimethylaminorex</a> (4,4'-DMAR), have been found to be inactive at the mouse and rat TAAR1.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a><a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a><a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> Many other <a href="/facts/Monoamine_releasing_agent/JwSvmyR8">monoamine releasing agents</a> (MRAs), such as many <a href="/facts/Substituted_amphetamine/KlmrodPb">amphetamines</a>, are rodent and/or human TAAR1 agonists.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a><a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> Activation of the TAAR1 may auto-inhibit and thereby constrain the <a href="/facts/Monoaminergic/hoY4ra25">monoaminergic</a> effects of these agents.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a><a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a><a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> Lack of TAAR1 agonism in the case of aminorex <a href="/facts/Structural_analog/3aysWSVG">analogues</a> might enhance their effects relative to MRAs possessing TAAR1 agonism.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a><a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a><a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a> </p> <h2 id="chemistry">Chemistry</h2> <p class="note">See also: <a href="/facts/List_of_aminorex_analogues/ps61PoJu">List of aminorex analogues</a></p> <p>Aminorex is a member of the <a href="/facts/List_of_aminorex_analogues/ps61PoJu">2-amino-5-phenyloxazoline</a> group.<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a> It is <a href="/facts/Structural_analog/3aysWSVG">structurally related</a> to the <a href="/facts/Substituted_amphetamine/KlmrodPb">substituted amphetamines</a> like <a href="/facts/Amphetamine/yKIpLJ9E">amphetamine</a> and to the <a href="/facts/Substituted_phenylmorpholine/aMBYnsHP">substituted phenylmorpholines</a> like <a href="/facts/Phenmetrazine/ogwT5xME">phenmetrazine</a>.<a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> </p><p>A variety of <a href="/facts/Chemical_derivative/JYcbLkbm">derivatives</a> and <a href="/facts/Structural_analog/3aysWSVG">analogues</a> of aminorex are known.<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> These include <a href="/facts/2%2527-fluoro-4-methylaminorex/UXMfHbA7">2'-fluoro-4-methylaminorex</a> (2F-MAR), <a href="/facts/2C-B-aminorex/UHJW75Ik">2C-B-aminorex</a>, <a href="/facts/3%2527%2c4%2527-methylenedioxy-4-methylaminorex/9yIV2DBV">3',4'-methylenedioxy-4-methylaminorex</a> (MDMAR), <a href="/facts/4%2527-bromo-4-methylaminorex/IGrUUNIa">4'-bromo-4-methylaminorex</a> (4B-MAR), <a href="/facts/4%2527-chloro-4-methylaminorex/j8HKykwW">4'-chloro-4-methylaminorex</a> (4C-MAR), <a href="/facts/4%2527-fluoro-4-methylaminorex/amwDo74E">4'-fluoro-4-methylaminorex</a> (4F-MAR), <a href="/facts/4-methylaminorex/YmtPUVNR">4-methylaminorex</a> (4-MAR), <a href="/facts/4%2c4%2527-dimethylaminorex/JUtrhoAb">4,4'-dimethylaminorex</a> (4,4'-DMAR), <a href="/facts/Clominorex/qmh8KE3k">clominorex</a>, <a href="/facts/Cyclazodone/Yh2GP07h">cyclazodone</a>, <a href="/facts/Fenozolone/vUEE2Lqa">fenozolone</a>, <a href="/facts/Fluminorex/1kYRVzrb">fluminorex</a>, <a href="/facts/Pemoline/KcjKIfh2">pemoline</a>, and <a href="/facts/Thozalinone/A9NbaaDh">thozalinone</a>, among others.<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a><a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a><a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> </p> <h3>Synthesis</h3> <p>The synthesis was first reported in a <a href="/facts/Structure-activity_relationship/S2RxpCUK">structure-activity relationship</a> study of 2-amino-5-aryl-2-oxazolines, where aminorex was found to be approximately 2.5 times more potent than <i>D</i>-amphetamine sulfate in inducing anorexia in rats, and was also reported to have CNS stimulant effects. </p> <p>The <a href="/facts/Racemic/STEagtrD">racemic</a> synthesis involves addition/cyclization reaction of 2-amino-1-phenylethanol with <a href="/facts/Cyanogen_bromide/KxYRuQCe">cyanogen bromide</a>.<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a> A similar synthesis has been also published.<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a> In a search for a cheaper synthetic route, a German team developed an alternative route<a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> which, by using chiral styrene oxide, allows an enantiopure product. </p> <h2 id="history">History</h2> <p>It was discovered in 1962 by Edward John Hurlburt,<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> and was quickly found in 1963 to have an <a href="/facts/Anorectic/MuLF8GNo">anorectic</a> effect in <a href="/facts/Rat/5rn6uEKM">rats</a>. It was introduced as a <a href="/facts/Prescription_drug/a2zNYPMq">prescription</a> appetite suppressant in <a href="/facts/Germany/paluuWBX">Germany</a>, <a href="/facts/Switzerland/LcGuxeTe">Switzerland</a> and <a href="/facts/Austria/4qWIMIyc">Austria</a> in 1965, but was withdrawn in 1972 after it was found to cause <a href="/facts/Pulmonary_hypertension/4848aBJl">pulmonary hypertension</a> in approximately 0.2% of patients, and was linked to a number of deaths.<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a><a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 54. ISBN 978-1-4757-2085-3. Retrieved 10 January 2025. <a href="978-1-4757-2085-3" target="_blank">978-1-4757-2085-3</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 14. ISBN 978-94-011-4439-1. Retrieved 10 January 2025. <a href="978-94-011-4439-1" target="_blank">978-94-011-4439-1</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 14. ISBN 978-94-011-4439-1. Retrieved 10 January 2025. <a href="978-94-011-4439-1" target="_blank">978-94-011-4439-1</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA (November 2000). "Recreational use of aminorex and pulmonary hypertension". Chest. 118 (5): 1496–1497. doi:10.1378/chest.118.5.1496. PMID 11083709. Archived from the original on 2013-01-12. <a href="https://archive.today/20130112175859/http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709" target="_blank">https://archive.today/20130112175859/http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>US 3161650, Ireland PG, "2-Amino-5-Aryloxazoline Products", issued 15 December 1964, assigned to Janssen Pharmaceuticals Inc. <a href="https://patents.google.com/patent/US3161650A" target="_blank">https://patents.google.com/patent/US3161650A</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Fishman AP (Jan 1991). "Aminorex to fen/phen: an epidemic foretold". Circulation. 99 (1): 156–161. doi:10.1161/01.CIR.99.1.156. PMID 9884392. <a href="https://doi.org/10.1161%2F01.CIR.99.1.156" target="_blank">https://doi.org/10.1161%2F01.CIR.99.1.156</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Ho EN, Leung DK, Leung GN, Wan TS, Wong AS, Wong CH, et al. (April 2009). "Aminorex and rexamino as metabolites of levamisole in the horse". Analytica Chimica Acta. 638 (1): 58–68. Bibcode:2009AcAC..638...58H. doi:10.1016/j.aca.2009.02.033. PMID 19298880. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Bertol E, Mari F, Milia MG, Politi L, Furlanetto S, Karch SB (July 2011). "Determination of aminorex in human urine samples by GC-MS after use of levamisole". Journal of Pharmaceutical and Biomedical Analysis. 55 (5): 1186–1189. doi:10.1016/j.jpba.2011.03.039. PMID 21531521. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol Ther. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol Biochem Behav. 71 (4): 825–836. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol Ther. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. 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PMID 17017961. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297708" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297708</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024. <a href="https://scholarworks.uno.edu/td/1436/" target="_blank">https://scholarworks.uno.edu/td/1436/</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W. <a href="978-0-470-11790-3" target="_blank">978-0-470-11790-3</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572453" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572453</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W. <a href="978-0-470-11790-3" target="_blank">978-0-470-11790-3</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID 11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays. <a href="https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261" target="_blank">https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> <li id="fn:24"><p>Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:24" class="footnote-back-ref">↩</a></p></li> <li id="fn:25"><p>Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306880" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306880</a> <a href="#fnref:25" class="footnote-back-ref">↩</a></p></li> <li id="fn:26"><p>Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W. <a href="978-0-470-11790-3" target="_blank">978-0-470-11790-3</a> <a href="#fnref:26" class="footnote-back-ref">↩</a></p></li> <li id="fn:27"><p>Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID 11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays. <a href="https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261" target="_blank">https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261</a> <a href="#fnref:27" class="footnote-back-ref">↩</a></p></li> <li id="fn:28"><p>Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:28" class="footnote-back-ref">↩</a></p></li> <li id="fn:29"><p>Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, et al. (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC 4128571. PMID 24841869. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128571" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128571</a> <a href="#fnref:29" class="footnote-back-ref">↩</a></p></li> <li id="fn:30"><p>Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W. <a href="978-0-470-11790-3" target="_blank">978-0-470-11790-3</a> <a href="#fnref:30" class="footnote-back-ref">↩</a></p></li> <li id="fn:31"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:31" class="footnote-back-ref">↩</a></p></li> <li id="fn:32"><p>Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID 11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays. <a href="https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261" target="_blank">https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261</a> <a href="#fnref:32" class="footnote-back-ref">↩</a></p></li> <li id="fn:33"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:33" class="footnote-back-ref">↩</a></p></li> <li id="fn:34"><p>Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, et al. (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC 4128571. PMID 24841869. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128571" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128571</a> <a href="#fnref:34" class="footnote-back-ref">↩</a></p></li> <li id="fn:35"><p>Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, et al. (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC 4128571. PMID 24841869. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128571" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128571</a> <a href="#fnref:35" class="footnote-back-ref">↩</a></p></li> <li id="fn:36"><p>McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, et al. (July 2015). "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis. 7 (7): 555–564. doi:10.1002/dta.1732. PMC 5331736. PMID 25331619. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331736" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331736</a> <a href="#fnref:36" class="footnote-back-ref">↩</a></p></li> <li id="fn:37"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:37" class="footnote-back-ref">↩</a></p></li> <li id="fn:38"><p>McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, et al. (July 2015). "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis. 7 (7): 555–564. doi:10.1002/dta.1732. PMC 5331736. PMID 25331619. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331736" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331736</a> <a href="#fnref:38" class="footnote-back-ref">↩</a></p></li> <li id="fn:39"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:39" class="footnote-back-ref">↩</a></p></li> <li id="fn:40"><p>McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, et al. (July 2015). "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis. 7 (7): 555–564. doi:10.1002/dta.1732. PMC 5331736. 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Retrieved 10 January 2025. <a href="https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=85705" target="_blank">https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=85705</a> <a href="#fnref:53" class="footnote-back-ref">↩</a></p></li> <li id="fn:54"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:54" class="footnote-back-ref">↩</a></p></li> <li id="fn:55"><p>Maier J, Mayer FP, Luethi D, Holy M, Jäntsch K, Reither H, et al. (August 2018). "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters". Neuropharmacology. 138: 282–291. doi:10.1016/j.neuropharm.2018.06.018. PMID 29908239. Receptor-binding experiments suggest that 4,4'-DMAR exhibits no – or if at all only poor-affinity towards mouse and rat TAAR1. On the contrary, sub- (rat) and low-micromolar (mouse) affinities towards TAAR1 have been reported for MDMA (Simmler et al., 2013). The exact role of TAAR1 in amphetamine action remains far from being completely understood (Sitte and Freissmuth, 2015). However, TAAR1 appears to exert auto-inhibitory effects on monoaminergic neurons, thus regulates the release of the corresponding monoamines (Revel et al., 2011, 2012). TAAR1 is activated by a subset of amphetamines (Simmler et al., 2016). This observation has been linked to auto-inhibitory and neuroprotective effects of TAAR1 in amphetamine action (Miner et al., 2017; Revel et al., 2012; DiCara et al., 2011; Lindemann et al., 2008). The lack of agonist activity at TAAR1 might further contribute to long-term toxicity of 4,4'-DMAR, thus representing an interesting field for future investigations. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:55" class="footnote-back-ref">↩</a></p></li> <li id="fn:56"><p>Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. doi:10.1016/j.neuro.2019.02.011. PMID 30776375. The methylated aminorex derivatives investigated in the present study did not interacted with TAAR1 receptors in contrast to amphetamine, MDMA, and several other phenethylamine derivatives (Revel et al., 2012; Simmler et al., 2016). Other aminorex-like ring-substituted 2- aminooxazolines have been shown to interact with TAAR1 receptors (Galley et al., 2016). However, they did not contain a 4-methyl group in contrast to the currently investigated compounds. Activity at TAAR1 may have auto-inhibitory effects on the monoaminergic action of amphetamine-type substances (Di Cara et al., 2011; Simmler et al., 2016). Therefore, the presently investigated compounds that did not bind to TAAR1 may exhibit greater stimulant properties compared to other amphetamines that also bind to TAAR1. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:56" class="footnote-back-ref">↩</a></p></li> <li id="fn:57"><p>Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1" (PDF). J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID 26791601. <a href="https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA" target="_blank">https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA</a> <a href="#fnref:57" class="footnote-back-ref">↩</a></p></li> <li id="fn:58"><p>Gainetdinov RR, Hoener MC, Berry MD (July 2018). "Trace Amines and Their Receptors". Pharmacol Rev. 70 (3): 549–620. doi:10.1124/pr.117.015305. PMID 29941461. <a href="https://doi.org/10.1124%2Fpr.117.015305" target="_blank">https://doi.org/10.1124%2Fpr.117.015305</a> <a href="#fnref:58" class="footnote-back-ref">↩</a></p></li> <li id="fn:59"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:59" class="footnote-back-ref">↩</a></p></li> <li id="fn:60"><p>Maier J, Mayer FP, Luethi D, Holy M, Jäntsch K, Reither H, et al. (August 2018). "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters". Neuropharmacology. 138: 282–291. doi:10.1016/j.neuropharm.2018.06.018. PMID 29908239. Receptor-binding experiments suggest that 4,4'-DMAR exhibits no – or if at all only poor-affinity towards mouse and rat TAAR1. On the contrary, sub- (rat) and low-micromolar (mouse) affinities towards TAAR1 have been reported for MDMA (Simmler et al., 2013). The exact role of TAAR1 in amphetamine action remains far from being completely understood (Sitte and Freissmuth, 2015). However, TAAR1 appears to exert auto-inhibitory effects on monoaminergic neurons, thus regulates the release of the corresponding monoamines (Revel et al., 2011, 2012). TAAR1 is activated by a subset of amphetamines (Simmler et al., 2016). This observation has been linked to auto-inhibitory and neuroprotective effects of TAAR1 in amphetamine action (Miner et al., 2017; Revel et al., 2012; DiCara et al., 2011; Lindemann et al., 2008). The lack of agonist activity at TAAR1 might further contribute to long-term toxicity of 4,4'-DMAR, thus representing an interesting field for future investigations. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:60" class="footnote-back-ref">↩</a></p></li> <li id="fn:61"><p>Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. doi:10.1016/j.neuro.2019.02.011. PMID 30776375. The methylated aminorex derivatives investigated in the present study did not interacted with TAAR1 receptors in contrast to amphetamine, MDMA, and several other phenethylamine derivatives (Revel et al., 2012; Simmler et al., 2016). Other aminorex-like ring-substituted 2- aminooxazolines have been shown to interact with TAAR1 receptors (Galley et al., 2016). However, they did not contain a 4-methyl group in contrast to the currently investigated compounds. Activity at TAAR1 may have auto-inhibitory effects on the monoaminergic action of amphetamine-type substances (Di Cara et al., 2011; Simmler et al., 2016). Therefore, the presently investigated compounds that did not bind to TAAR1 may exhibit greater stimulant properties compared to other amphetamines that also bind to TAAR1. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:61" class="footnote-back-ref">↩</a></p></li> <li id="fn:62"><p>Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490. Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts184. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711</a> <a href="#fnref:62" class="footnote-back-ref">↩</a></p></li> <li id="fn:63"><p>Maier J, Mayer FP, Luethi D, Holy M, Jäntsch K, Reither H, et al. (August 2018). "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters". Neuropharmacology. 138: 282–291. doi:10.1016/j.neuropharm.2018.06.018. PMID 29908239. Receptor-binding experiments suggest that 4,4'-DMAR exhibits no – or if at all only poor-affinity towards mouse and rat TAAR1. On the contrary, sub- (rat) and low-micromolar (mouse) affinities towards TAAR1 have been reported for MDMA (Simmler et al., 2013). The exact role of TAAR1 in amphetamine action remains far from being completely understood (Sitte and Freissmuth, 2015). However, TAAR1 appears to exert auto-inhibitory effects on monoaminergic neurons, thus regulates the release of the corresponding monoamines (Revel et al., 2011, 2012). TAAR1 is activated by a subset of amphetamines (Simmler et al., 2016). This observation has been linked to auto-inhibitory and neuroprotective effects of TAAR1 in amphetamine action (Miner et al., 2017; Revel et al., 2012; DiCara et al., 2011; Lindemann et al., 2008). The lack of agonist activity at TAAR1 might further contribute to long-term toxicity of 4,4'-DMAR, thus representing an interesting field for future investigations. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:63" class="footnote-back-ref">↩</a></p></li> <li id="fn:64"><p>Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. doi:10.1016/j.neuro.2019.02.011. PMID 30776375. The methylated aminorex derivatives investigated in the present study did not interacted with TAAR1 receptors in contrast to amphetamine, MDMA, and several other phenethylamine derivatives (Revel et al., 2012; Simmler et al., 2016). Other aminorex-like ring-substituted 2- aminooxazolines have been shown to interact with TAAR1 receptors (Galley et al., 2016). However, they did not contain a 4-methyl group in contrast to the currently investigated compounds. Activity at TAAR1 may have auto-inhibitory effects on the monoaminergic action of amphetamine-type substances (Di Cara et al., 2011; Simmler et al., 2016). Therefore, the presently investigated compounds that did not bind to TAAR1 may exhibit greater stimulant properties compared to other amphetamines that also bind to TAAR1. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:64" class="footnote-back-ref">↩</a></p></li> <li id="fn:65"><p>Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 54. ISBN 978-1-4757-2085-3. Retrieved 10 January 2025. <a href="978-1-4757-2085-3" target="_blank">978-1-4757-2085-3</a> <a href="#fnref:65" class="footnote-back-ref">↩</a></p></li> <li id="fn:66"><p>Elks J (2014). 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