Authors :
Alex Vasilkevich, MSc – Bright Minds Biosciences
Jianmin Duan, PhD – Bright Minds Biosciences
Ian McDonald, BS – Bright Minds Biosciences
Jo Sourbron, PhD – Ghent University Hospital
Mark Smith, MD – Bright Minds Biosciences
John McCorvy, PhD – Medical College of Wisconsin
Presenting Author: Jan Pedersen, PhD – Bright Minds Biosciences
Rationale:
The 5-HT2C receptor, a G protein-coupled receptor (GPCR), has emerged as a potential target for epilepsy treatment due to its role in modulating neurotransmitter release and neuronal excitability. Traditional 5-HT2C agonists can lead to receptor desensitization through β-arrestin (β-arr) recruitment, reducing long-term efficacy (Rankovic Z et al. Bioorg Med Chem Lett, 26 (2016)). By developing biased agonists that preferentially activate Gq protein signaling without engaging β-arr pathways, it may be possible to enhance therapeutic outcomes and minimize tolerance in epilepsy treatment. BMB-101 is a novel 5-HT2C agonist developed by Bright Minds Biosciences Inc (USA) that belongs to a well-characterized class of tranylcypromine scaffold. It is currently in clinical evaluation for the treatment of drug-resistant epilepsy.
Methods:
This study investigates the 5-HT2C mechanism of BMB-101 and includes selectivity analysis at 5-HT receptors and functional selectivity analysis (G-protein vs β-arr). 5-HT2C receptor-mediated β-arr1 or β-arr2 recruitment was measured by Bioluminescence resonance energy transfer (BRET) methods in vitro. The analysis is complemented by a literature review with the historical data of biased GPCR agonists and the role of β-arr in developing tolerance.
Results:
BMB-101 was investigated at 5-HT2A/2B/2C receptors using Gq dissociation as measured by BRET. In this assay, BMB-101 is a potent 5-HT2C agonist (EC50 = 16.2 nM) with minimal activity at 5-HT2A (EC50 = 2280 nM) and 5-HT2B (EC50 > 10000 nM) receptors. BMB-101 was evaluated for recruitment of β-arr1 and β-arr2 as measured by BRET and compared to Lorcaserin. BMB-101 exhibits weak partial agonism of β-arr1 and β-arr2 recruitment (βarr1: EC50 = 75 nM; Emax = 12.9%; βarr2: EC50 = 77 nM; Emax = 20.8%) compared to Gq dissociation measured by BRET. Lorcaserin, on the other hand, is able to maximally recruit β-arr1 and β-arr2 (βarr1: EC50 = 52.8 nM; Emax = 100.3%; βarr2: EC50 = 24.1 nM; Emax = 107.4%). BMB-101 shows a greater preference for Gq dissociation agonist activity versus β-arr1 and β-arr2 recruitment activity compared to Lorcaserin, thus demonstrating Gq-biased agonism.
Conclusions:
Based on the currently available data, BMB-101 is the only compound in clinical development (phase II anticipated Q4 2024) that has shown to be a “biased” or “functionally selective” 5-HT2C agonist, which means that it only targets one of the GPCR pathways. This is of utmost importance since βArr activation is associated with steric hindrance of further 5-HT2C Gq activation, 5-HT2C receptor internalization and impeding further stimuli of the 5-HT2C receptor. This means that compounds such as BMB-101, which are devoid of βArr activation, likely will not lead to tolerance (no expected ‘honeymoon effect’ as opposed to the other 5-HT2C agonists currently in development). The development of 5-HT2C receptor agonists with biased agonism and reduced β-arr recruitment offers a promising strategy for the chronic treatment of epilepsy. Further clinical studies of BMB-101 are planned to evaluate its sustained efficacy in chronic use
Funding:
This study was fully funded by Bright Minds Biosciences Inc.