ENX-104
ENX-104, also known as deuterated nemonapride enantiomer, is a selective dopamine D2 and D3 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 D2 and D3 autoreceptors and hence to enhance rather than inhibit dopaminergic neurotransmission. It is taken by mouth.
Pharmacology
Pharmacodynamics
ENX-104 is intended for use at low doses to produce preferential presynaptic dopamine D2 and D3 autoreceptor antagonism and consequent enhancement of dopaminergic neurotransmission. The target occupancy of the dopamine D2 and D3 receptors is approximately 40 to 70%. For comparison, dopamine D2 receptor occupancy of 65 to 80% is associated with antipsychotic-like effects and hence with substantial postsynaptic dopamine D2 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 or catalepsy at the low doses employed, as these effects require higher occupancy of the D2 receptor.
ENX-104 is highly potent as a dopamine receptor antagonist. Its affinities are 0.01nM for the dopamine D2L receptor, 0.1nM for the dopamine D2S receptor, 0.2nM for the dopamine D3 receptor, and 1.6nM for the dopamine D4 receptor. The drug is also a weak partial agonist or antagonist of the serotonin 5-HT2A receptor, with an of 14nM and an Emax of approximately 40%. Conversely, ENX-104 showed little or no functional activity at the serotonin 5-HT1A or 5-HT7 receptor.