Aticaprant

Pharmacological Actions
Aticaprant's primary pharmacological action is as a selective antagonist of the KOR, with a binding affinity (Ki) of 0.81 nM, showing approximately 30-fold selectivity over the mu-opioid receptor (MOR, Ki = 24.0 nM) and delta-opioid receptor (DOR, Ki = 155 nM) Wikipedia: Aticaprant. This selectivity suggests its main effect is on KOR-mediated processes, such as mood regulation, stress response, and reward systems, which are implicated in MDD, anxiety disorders, and substance use disorders like alcoholism and cocaine dependence. At higher doses, such as 25 mg and 60 mg, it has been shown to dose-dependently block fentanyl-induced miosis, indicating significant MOR antagonism at these levels, which could influence pain perception and opioid-related side effects Wikipedia: Aticaprant.
The time course of these actions is tied to its pharmacokinetics. Research indicates rapid absorption, with maximal concentrations (Tmax) occurring 1 to 2 hours post-administration, as determined in both animal and human studies MedChemExpress: Aticaprant, Wikipedia: Aticaprant. Given its half-life of 30-40 hours, the effects are likely sustained, with steady-state concentrations reached after 6 to 8 days of once-daily dosing Wikipedia: Aticaprant. A positron emission tomography (PET) study by Naganawa et al. (2016) showed that at 10 mg, Aticaprant nearly saturates KOR receptors 2.5 hours post-dose, with maximum occupancy estimated at 93%, and occupancy likely persists at 24 hours due to the long half-life Journal of Pharmacology and Experimental Therapeutics: Receptor Occupancy.
Pharmacokinetic Parameters
Key pharmacokinetic parameters include:

Half-life: Estimated at 30 to 40 hours in healthy subjects, supporting its suitability for once-daily dosing Wikipedia: Aticaprant.
Bioavailability (oral): Reported as 25%, based on animal studies (rats and mice), with human data confirming oral administration but not specifying exact bioavailability beyond this MedChemExpress: Aticaprant, Wikipedia: Aticaprant. Other routes of administration were not detailed in the available literature.
Time to Peak Concentration (Tmax): 1 to 2 hours, indicating rapid absorption MedChemExpress: Aticaprant, Wikipedia: Aticaprant.
Steady-State Concentrations: Achieved after 6 to 8 days of once-daily dosing, aligning with its long half-life Wikipedia: Aticaprant.

These parameters suggest Aticaprant's effects are prolonged, with significant receptor occupancy early after dosing and sustained activity over days, which is critical for its potential therapeutic use.
Dosage and Safety Profile
Dosage information from clinical trials provides insight into its use and safety:

Therapeutic Dose: In a phase 2 study for MDD, 10 mg once daily was used as an adjunct to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), showing significant improvement in depressive symptoms Nature: Efficacy and Safety. This is considered the minimum effective dose based on efficacy data.
Doses Tested: Range from 0.5 mg to 60 mg, with PET studies using up to 25 mg and higher doses (25 mg, 60 mg) assessed for MOR antagonism Wikipedia: Aticaprant, Journal of Pharmacology and Experimental Therapeutics: Receptor Occupancy.
Safe Range: Up to 25 mg was well-tolerated in studies, with no serious adverse events reported. At 10 mg, common side effects included headache, diarrhea, nasopharyngitis, and pruritus, mostly mild to moderate Nature: Efficacy and Safety. Doses up to 60 mg have been tested, but specific safety data at these levels are limited.
Maximum Dose Without High Risks: Not explicitly stated, but given testing up to 60 mg and lack of reported serious adverse events at lower doses, it seems likely that up to 25 mg is safe, with caution at higher doses due to potential MOR effects.
LD50: Not publicly available, reflecting Aticaprant's status as a drug in development, with toxicity data typically limited to preclinical animal studies not detailed in public sources.
When It Starts to Become Too Dangerous: Not specified, but at doses ≥25 mg, significant MOR antagonism may occur, potentially leading to additional side effects like those associated with opioid receptor antagonism, such as hypotension or dysrhythmias, as noted in related literature Taylor & Francis: Aticaprant Review.

The discontinuation of phase III trials in March 2025 due to lack of effectiveness highlights the challenges in its development, but does not negate the pharmacological data from earlier phases Wikipedia: Aticaprant.
Detailed Considerations
The survey note also considers potential secondary effects and interactions. Aticaprant's KOR antagonism may influence pain perception, stress responses, and reward systems, given KOR's role in these areas. Its interaction with ethanol was noted to have no significant cognitive or motor effects, suggesting compatibility with alcohol consumption in some contexts Taylor & Francis: Aticaprant Review. However, potential side effects like pruritus and bowel irritation are monitored due to KOR antagonism's effects on itching and irritable bowel syndrome Taylor & Francis: Aticaprant Review.
Table for adverse events from the phase 2 study:

Adverse Event	Incidence (Aticaprant 10 mg, %)	Notes
Headache	≥5.0	Mostly mild to moderate
Diarrhea	≥5.0	Transient
Nasopharyngitis	≥5.0	Common cold-like symptoms
Pruritus	≥5.0	Itching, mild to moderate
Serious Adverse Events	0 (none related to drug)	One case in placebo group