Our Science

At Engrail, we apply precision chemistry and pharmacology to develop transformative medicines for patients who have been underserved by existing treatments. Our unique approach centers on scientifically validated mechanisms of action with established proof of concept. This improves our probability of success in rapidly delivering best-in-class therapies to patients in need.

GABA MODULATION

GABA is the primary inhibitory neurotransmitter in the brain.1 Enhancing inhibitory neurotransmission is a proven therapeutic approach for the treatment of seizure disorders, anxiety, pain, and a broad array of other indications.2-4

Benzodiazepines are the most widely known GABA modulators and provide remarkable efficacy for short-term use, but their chronic use is often limited by loss of efficacy over time as well as significant side effects (e.g., sedation, cognitive impairment, motor impairment) and risks (e.g., physical dependence, addiction potential). Benzodiazepines are conventional, nonselective GABAA positive allosteric modulators (PAMs) that drive function at GABAA receptors containing α1, α2, α3, or α5 subunits.5,6 Whereas activity at all α subunits can contribute to the efficacy of benzodiazepines, specific activity at α1 is thought to drive many undesirable side effects and risks.5-7 

Our scientific expertise in GABAA receptor pharmacology and neurocircuitry has led to the development of precision-targeted therapies that maximize the clinical benefits of GABA modulation while minimizing the undesirable side effects and risks associated with benzodiazepines.

Our selective GABAA α2,3,5  PAMs represent the next-generation of treatment for neurologic and neuropsychiatric disorders, offering the potential for:

  • Enhanced and sustained efficacy with chronic use
  • Improved tolerability
  • Ease of administration

Our lead clinical-stage compounds, ENX-101 and ENX-102, are precision-targeted GABAA PAMs that enhance neurotransmission through GABAA receptors containing α2, α3, and α5 subunits while blocking α1. ENX-101 is being studied for the treatment of seizures, and ENX-102 is being studied for the treatment of anxiety.8

Dopamine Modulation

Dysregulated dopamine neurotransmission, particularly in brain reward circuitry, plays a role in depression and other mood disorders.1,2

A hallmark symptom of major depressive disorder is anhedonia, which is the loss of ability to feel pleasure. There are no treatments for depression that target this core symptom, and anhedonia is associated with a poor response to currently available antidepressant treatments.1

A selective therapy that increases dopamine neurotransmission has the potential to improve the symptoms of depression, including anhedonia — a significant unmet need in the treatment of depression.1

The role of dopamine D2/D3 receptors in regulating mood and reward processing is well established.3 At low doses, D2/D3 receptor antagonists preferentially block presynaptic autoreceptors to increase dopamine release.4 Our compound ENX-104 is a highly potent and selective D2/D3 receptor antagonist with excellent brain pharmacokinetics. It is well-positioned to provide an anti-anhedonic therapeutic response at low doses, with a favorable safety and tolerability profile.5

Neurotransmission of both dopamine and serotonin have important regulatory effects on mood and can modulate one another.2,6-8 In addition to the role of dopamine in regulating reward processing, serotonin plays a key role in emotion processing.3,9 Our compound ENX-105 is a D2/D3 receptor antagonist that is also a serotonin receptor modulator. This unique combination of pharmacological actions may drive therapeutic benefits for a wide variety of mood disorders.5

+ References and Abbreviations

GABA modulation:

GABA, gamma-aminobutyric acid; PAM, positive allosteric modulator.

1. Wu C & Sun D. Metab Brain Dis. 2015;30:367–379. 2. Bialer M, et al. Epilepsia 2020;61:2365–2385. 3. Wright SL. Adv Ther. 2020;37:2604–2619. 4. DeMartini J, et al. Ann Intern Med. 2019;170:ITC49 –ITC64. 5. Vinkers CH & Olivier B. Adv Pharmacol Sci. 2012;2012:416864. 6. Castellano D, et al. Front Neurosci. 2021;14:616298. 7. Licata SC & Rowlett JK. Pharmacol Biochem Behav 2008;90:74–89. 8. Engrail Therapeutics. Data on file.

Dopamine modulation:

D2, dopamine receptor 2; D3, dopamine receptor 3.

1. Belujon P & Grace AA. Int J Neuropsychopharmacol. 2017;20:1036–1046. 2. Grace AA. Nat Rev Neurosci. 2016;17:524–532. 3. Stahl SM. CNS Spectr. 2017;22:375–384. 4. Schoemaker H, et al. J Pharmacol Exp Ther. 1997;280:83–97. 5. Engrail Therapeutics. Data on file. 6. Ressler KJ & Nemeroff CB. Depress Anxiety. 2000;12(Suppl. 1):2–19. 7. Daw ND, et al. Neural Netw. 2002;15:603–616. 8. Wong PT, et al. Neurosci Res. 1995;23:115–119. 9. Lucki I. Biol Psychiatry. 1998;44:151–162.