ENX-104, also known as deuterated nemonapride enantiomer, is a selective dopamine D<sub>2</sub> and D<sub>3</sub> receptor antagonist which is under development for the treatment of major depressive disorder. It is specifically under development for the treatment of major depressive disorder characterized by anhedonia. The drug is being developed for use at low doses to preferentially block presynaptic dopamine D<sub>2</sub> and D<sub>3</sub> autoreceptors and hence to enhance rather than inhibit dopaminergic neurotransmission. It is taken by mouth.
ENX-104 is intended for use at low doses to produce preferential presynaptic dopamine D<sub>2</sub> and D<sub>3</sub> autoreceptor antagonism and consequent enhancement of dopaminergic neurotransmission. The target occupancy of the dopamine D<sub>2</sub> and D<sub>3</sub> receptors is approximately 40 to 70%. For comparison, dopamine D<sub>2</sub> receptor occupancy of 65 to 80% is associated with antipsychotic-like effects and hence with substantial postsynaptic dopamine D<sub>2</sub> receptor antagonism in animals. ENX-104 has been found to increase dopamine and serotonin levels in the nucleus accumbens and prefrontal cortex. It was also found to augment amphetamine-induced dopamine release. In accordance with these findings, the drug was found to produce anti-anhedonia-like effects, specifically increased reward responsiveness, in animals. Low doses of amisulpride likewise showed anti-anhedonia-like effects.
ENX-104 is not expected to induce motor side effects like extrapyramidal symptoms (EPS) or catalepsy at the low doses employed, as these effects require higher occupancy of the D<sub>2</sub> receptor (e.g., ~80%).
ENX-104 is highly potent as a dopamine receptor antagonist. Its affinities are 0.01nM for the dopamine D<sub>2L</sub> receptor, 0.1nM for the dopamine D<sub>2S</sub> receptor, 0.2nM for the dopamine D<sub>3</sub> receptor (2- to 20-fold lower than for the D<sub>2</sub> receptor), and 1.6nM for the dopamine D<sub>4</sub> receptor (8- to 160-fold lower than for the D<sub>2</sub> receptor). The drug is also a weak partial agonist or antagonist of the serotonin 5-HT<sub>2A</sub> receptor, with an of 14nM (70- to 1,400-fold lower than its affinity for the D<sub>2</sub> receptor) and an E<sub>max</sub> of approximately 40%. Conversely, ENX-104 showed little or no functional activity at the serotonin 5-HT<sub>1A</sub> or 5-HT<sub>7</sub> receptor.
ENX-104 is a benzamide derivative. It is a partially-deuterated analog of the drug nemonapride, which is used to treat schizophrenia.
As of September 2024, ENX-104 is in phase 1 clinical trials for major depressive disorder. It is under development by Engrail Therapeutics.