# Norfenfluramine

Norfenfluramine, or 3-trifluoromethylamphetamine, is a never-marketed drug of the amphetamine family and a major active metabolite of the appetite suppressants fenfluramine and benfluorex. The compound is a racemic mixture of two enantiomers with differing activities, dexnorfenfluramine and levonorfenfluramine.

## Pharmacology

Norfenfluramine acts as a serotonin–norepinephrine releasing agent (SNRA) and as a potent serotonin 5-HT$_{2A}$, 5-HT$_{2B}$, and 5-HT$_{2C}$ receptor agonist. Both enantiomers of norfenfluramine are active as monoamine releasing agents, although dexnorfenfluramine is more potent than levonorfenfluramine. Similarly, both enantiomers are active as serotonin 5-HT$_2$ receptor agonists, but dexnorfenfluramine is likewise more potent than levonorfenfluramine.
Norfenfluramine is of similar potency as fenfluramine as a serotonin releaser but is substantially more potent as a norepinephrine and dopamine releaser. The drug is also far more potent than fenfluramine as an agonist of the serotonin 5-HT$_2$ receptors.
The action of norfenfluramine on serotonin 5-HT$_{2B}$ receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve, known as cardiac fibrosis. This side effect led to the withdrawal of fenfluramine as an anorectic medication worldwide and to the withdrawal of benfluorex in Europe.
In spite of acting as a serotonin 5-HT$_{2A}$ receptor agonist, norfenfluramine is described as non-hallucinogenic. However, hallucinations have occasionally been reported with large doses of fenfluramine, which itself is a much weaker serotonin 5-HT$_{2A}$ receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite.
Norfenfluramine has been found to act as an agonist of the trace amine-associated receptor 1 (TAAR1). Dexnorfenfluramine is a very weak human TAAR1 agonist (43% of maximum in screen at a concentration of 10,000 nM), whereas levonorfenfluramine is inactive as a human TAAR1 agonist.
Monoamine release of norfenfluramine and related agents (EC$_{50}$Tooltip Half maximal effective concentration, nM) :
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin |
| Dextroamphetamine | 6.6–7.2 | 5.8–24.8 | 698–1,765 |
| Levoamphetamine | 9.5 | 27.7 | ND |
| Dextromethamphetamine | 12.3–14.3 | 8.5–40.4 | 736–1,292 |
| Levomethamphetamine | 28.5 | 416 | 4,640 |
| Dextroethylamphetamine | 28.8 | 44.1 | 333.0 |
| Fenfluramine | 739 | >10,000 (RI) | 79.3–108 |
| Dexfenfluramine | 302 | >10,000 | 51.7 |
| Levfenfluramine | >10,000 | >10,000 | 147 |
| Norfenfluramine | 168–170 | 1,900–1,925 | 104 |
| Dexnorfenfluramine | 72.7 | 924 | 59.3 |
| Levnorfenfluramine | 474 | >10,000 | 287 |
| Phentermine | 28.8–39.4 | 262 | 2,575–3,511 |
| Chlorphentermine | >10,000 (RI) | 935–2,650 | 18.2–30.9 |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: |||||
Norfenfluramine and related agents at the serotonin 5-HT$_2$ receptors :
| Compound | 5-HT$_{2A}$ | 5-HT$_{2A}$ | 5-HT$_{2A}$ | 5-HT$_{2B}$ | 5-HT$_{2B}$ | 5-HT$_{2B}$ | 5-HT$_{2C}$ | 5-HT$_{2C}$ | 5-HT$_{2C}$ |
| Compound | K$_i$ (nM) | EC$_{50}$Tooltip Half-maximal effective concentration (nM) | E$_{max}$Tooltip Maximal efficacy (%) | K$_i$ (nM) | EC$_{50}$Tooltip Half-maximal effective concentration (nM) | E$_{max}$Tooltip Maximal efficacy (%) | K$_i$ (nM) | EC$_{50}$Tooltip Half-maximal effective concentration (nM) | E$_{max}$Tooltip Maximal efficacy (%) |
| Fenfluramine | 5,216 | 4,131 | 15% | 4,134 | ND | ND | 3,183 | ND | ND |
| Dexfenfluramine | 11,107 | >10,000 | ND | 5,099 | 379 | 38% | 6,245 | 362 | 80% |
| Levofenfluramine | 5,463 | 5,279 | 43% | 5,713 | 1,248 | 47% | 3,415 | 360 | 84% |
| Norfenfluramine | 2,316 | ND | ND | 52.1 | ND | ND | 557 | ND | ND |
| Dexnorfenfluramine | 1,516 | 630 | 88% | 11.2 | 18.4 | 73% | 324 | 13 | 100% |
| Levonorfenfluramine | 3,841 | 1,565 | 93% | 47.8 | 357 | 71% | 814 | 18 | 80% |
| Phentermine | >10,000 | IA or ND | IA or ND | >10,000 | IA or ND | IA or ND | >10,000 | 1,394 | 66% |
| Chlorphentermine | ND | >10,000 | ND | ND | 5,370 | ND | ND | 6,456 | ND |
| Notes: (1) The smaller the K$_i$ or EC$_{50}$ value, the more avidly the drug binds to or activates the receptor. The higher the E$_{max}$ value, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT$_{2A}$ and 5-HT$_{2C}$ K$_i$ values, which are for the rat receptors. Refs: ||||||||||