Objective: To characterize the binding/inhibition and potential clinical relevance of ecopipam and its metabolites across a wide array of potential off-target receptors, ion channels, enzymes, and transporters.

Background: Ecopipam is a first-in-class selective dopamine D1 receptor (D1R) antagonist being investigated for treatment of Tourette syndrome (TS). After oral administration, ecopipam is primarily metabolized to ecopipam glucuronide (E-G), with a minor metabolite, EBS-101-40853 (EBS) and its glucuronide conjugate (EBS-G).

Method: In vitro screening studies were conducted to evaluate the binding/inhibition of ecopipam, E-G, EBS, and EBS-G to approximately 98 unique targets at 10-mM concentrations. For any receptor that had at least 50% inhibition, a follow-on study determined the concentration with 50% inhibition (IC₅₀). To understand whether binding/inhibition to each of these targets had potential clinical relevance, the IC₅₀ values were compared to clinical exposures as measured by the free-fraction, steady-state C_max values (C_max,ss,free) after dosing with ecopipam using the weight-based dosing paradigm in individuals with TS. Clinical relevance was determined if the IC₅₀/C_max,ss,free was less than 10× (a 10-fold “safety margin”). If the ratio exceeded 10× but remained below 15×, then a potential effect on the receptor binding could not be ruled out. The clinical relevance of specific targets in the brain was also considered based on the central nervous system penetration of ecopipam and its metabolites.

Results: Ecopipam, E-G, and EBS demonstrated marked inhibition of D1Rs, and ecopipam and EBS also inhibited D5Rs at clinically relevant concentrations expected after steady-state dosing in TS. EBS-G was not active at any dopamine receptor subtype. Potential off-target binding/inhibition effects of ecopipam at dopamine D_2S, serotonin 1A (5-HT_1A), histamine H₁, and alpha-2C adrenergic receptors could not be ruled out; however, the predicted exposure margins associated with these interactions were above the 10-fold safety margin.

Conclusion: Ecopipam demonstrated selectivity for D1Rs over approximately 98 off-target receptors, ion channels, enzymes, and transporters. These data are consistent with the clinical profile of ecopipam in children, adolescents, and adults with TS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/receptor-selectivity-profile-and-clinical-significance-of-ecopipam-and-its-metabolites-as-a-potential-therapy-for-tourette-syndrome/