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.
Norfenfluramine acts as a serotoninâÂÂnorepinephrine releasing agent (SNRA) and as a potent serotonin 5-HT<sub>2A</sub>, 5-HT<sub>2B</sub>, and 5-HT<sub>2C</sub> 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<sub>2</sub> 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<sub>2</sub> receptors.
The action of norfenfluramine on serotonin 5-HT<sub>2B</sub> 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<sub>2A</sub> 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<sub>2A</sub> 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.