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-HT2A, 5-HT2B, and 5-HT2C 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-HT2 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-HT2 receptors.

The action of norfenfluramine on serotonin 5-HT2B 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-HT2A 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-HT2A receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite. Dexnorfenfluramine produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.

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 10,000nM), whereas levonorfenfluramine is inactive as a human TAAR1 agonist.

+ Compound Ref Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 Levoamphetamine 9.5 27.7 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 () 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 () 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:

+ Compound 5-HT2A 5-HT2B 5-HT2C Ki (nM) (nM) (%) Ki (nM) (nM) (%) Ki (nM) (nM) (%) Fenfluramine 5,216 4,131 15% 4,134 3,183 Dexfenfluramine 11,107 >10,000 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 52.1 557 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 or or >10,000 or or >10,000 1,394 66% Chlorphentermine >10,000 5,370 6,456 Notes: (1) The smaller the Ki or EC50 value, the more avidly the drug binds to or activates the receptor. The higher the Emax value, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT2A and 5-HT2C Ki values, which are for the rat receptors. Refs:

See also Substituted amphetamine

References