Abstract
Background
We have designed a novel psychedelic-derived compound (HBL20017) characterized by high functional efficacy at 5-HT2A, 5-HT1A, and 5-HT2C receptors. We assessed its hallucinogenic properties and its potential for OCD treatment on the marble burying test (MBT) and in mice homozygous for deletion of the Synapse Associated Protein 3 (SAPAP3) gene. These mice manifest severe, potentially lethal, obsessive self-grooming and head-body twitches, which are regarded as a model for tic disorders. SAPAP3 is associated with OCD in humans. The obsessive grooming of SAPAP3-/- mice is alleviated by fluoxetine and, in our recent study, by the serotonergic psychedelic psilocybin (Brownstien et al, 2024).
Aims & Objectives
To determine the potential efficacy of HBL20017 in the treatment of OCD and tic disorders
Method
HBL20017 was tested for functional activity at 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors by calcium mobilization in HEK cells and in animal models at doses of 6 or 10 mg/kg i.p. HTR was determined for 30 minutes using a magnetometer immediately after drug injection in C57bl/6j mice (male, 10-11 weeks). MBT was performed 30 minutes after drug administration to ICR mice (male, 10-11 weeks), and the number of marbles buried over 30 minutes was determined. Self-grooming and head-body twitches were determined over one hour in SAPAP3-/- mice aged at least 6 months by an observer blind to their treatment status, at baseline and 2, 12, 21, 28, and 42 days after treatment.
Results
HBL20017 showed potencies (ED50) of 1.84nM at the 5-HT1A receptor; 7.95nM at the 5-HT2A receptor; 17.1 nM at the 5-HT2B receptor; and, 0.80 nM at the 5-HT2C receptor on calcium mobilization assays. In vitro biological assays showed no indication of cytotoxicity or hERG inhibition. HBL20017 did not induce HTR, suggesting it is non-hallucinogenic. On the MBT, HBL20017 significantly reduced the number of marbles buried over 30 minutes compared to vehicle control. When administered to 6-month-old SAPAP3-/- mice, a single dose of HBL20017 significantly attenuated the increase in self-grooming observed in SAPAP3-/- mice treated with vehicle. The ability of a single dose of HBL20017 to alleviate obsessive self-grooming was seen 48 hours after treatment and persisted 12, 21, 28, and 42 days after a single dose. No mice in the HBL20017 group developed grooming-associated skin lesions during the observation period. HBL20017 also alleviated head-body twitches.
Discussion & Conclusions
HBL20017, which has shown a favorable safety profile on initial evaluation, did not induce HTR and yielded positive results on two tests for anti-obsessional potential – the marble burying test and the SAPAP3 obsessional self-grooming model. These findings suggest that HBL20017 has the potential to be a non-hallucinogenic psychedelic treatment for OCD. Reduction of excessive self-grooming was already evident 48 hours after administration of HBL20017 to SAPAP3 KO mice and persisted up to 42 days after a single dose. Comparison with the results of our previous research (Brownstien et al, 2024) suggests that HBL20017 may be more effective than psilocybin in reducing excessive self-grooming over the long term. HBL20017 also alleviated head-body twitches, suggesting it may have potential in the treatment of tic disorders such as Tourette’s Syndrome.