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Drawing on decades of neurological research, Engrail Therapeutics is developing treatments for mood disorders that modulate well-known targets, but with improved selectivity and specificity designed to hit that therapeutic sweet spot of minimised side effects and maximised efficacy.  “Our approach is to take known pharmacology and known chemistry, and apply that knowledge to indications with significant unmet need that are well understood,” Anil Vootkur, VP of corporate development told FirstWord. “We believe that allows Engrail to have a higher probability of success than other organisations that are operating in the same space as us.”With one compound already in mid-stage testing, Engrail raised an oversubscribed $157-million Series B on Tuesday to wrap up that study and bring three more programmes into the clinic. Vootkur said the impressive raise was bolstered by a “swell of excitement in the neurosciences in general, and the investment environment,” citing the massive neurology takeouts that closed out 2023. Bristol Myers Squibb bought Karuna for $14 billion in December, roughly two weeks after AbbVie agreed to acquire Cerevel for $8.7 billion. For more, see KOL Views Q&A: Leading psychiatrist sees a muscarinic revolution coming in schizophrenia and beyond.The round, which brings the biotech’s total funding to $220 million, was co-led by new investors F-Prime Capital, Forbion, and Norwest Venture Partners. The fundraising also saw participation from RiverVest Venture Partners, Red Tree Venture Capital, funds managed by abrdn Inc., Ysios Capital, Longwood Fund, Eight Roads Ventures, and existing founding investor Pivotal Life Sciences.Selective targeting for better safetyRather than charting new grounds with its portfolio of mood disorder treatments, Engrail is fine-tuning compounds against established targets. “It helps to de-risk” Engrail’s programmes, chief scientific officer Kimberly Vanover told FirstWord.  “We're building on what's known, but improving that for the future to be able to have strong efficacy, durable efficacy, and a favourable safety profile.”The company’s lead compound, ENX-102, is in a Phase II trial to treat generalised anxiety disorder, with a data readout expected in the first half of 2025. For example, the neurotransmitter GABA is well-known to inhibit central nervous system activity with an anxiolytic effect, as shown by barbiturates and benzodiazepines.Like the latter drug class, ENX-102 is a positive allosteric modulator of GABAa  – but instead selectively activates the α2, α3, or α5 subunit receptors while avoiding α1, which is thought to be responsible for the negative side effects of the decades-old anxiety medications. Moreover, chronic use of benzodiazepines is limited by a loss of efficacy over time and can have a sedative effect, as well as lead to cognitive and motor impairments.By engaging with α2, α3, and α5, ENX-102 “is able to drive the efficacy without the many side effects that are associated with α1 activation,” Vanover explained. “Essentially, our programme builds on decades of learning in the field with successive improvements over time.”Upping dopamineThe same philosophy is also true for two of Engrail’s preclinical projects, which are designed to increase the release of dopamine to treat major depressive disorder (MDD) and post-traumatic stress disorder (PTSD).Approved D2/D3 receptor antagonists today are typically given at high doses to treat schizophrenia by blocking post-synaptic receptors, thereby decreasing dopamine neurotransmission, Vanover said.Instead, Engrail’s ENX-104 is designed to be given at a low dose to block presynaptic D2/D3 autoreceptors and ramp up dopamine release. Because of dopamine’s well-established role in regulating mood and reward processing, the biotech is developing the compound to treat a specific symptom of MDD that currently has no approved treatments: anhedonia, or the loss of ability to feel pleasure. Engrail expects to start clinical testing of ENX-104 to treat anhedonia this year, and in 2025, it plans to enter the clinic with ENX-105 for PTSD.In addition to blocking the D2/D3 receptors, ENX-105 is also a serotonin 5HT1 and 5HT2 receptor agonist. The compound “has a really exciting combination of pharmacology that we've never before seen in a single molecule,” Vanover said. By pairing the anxiolytic and antidepressant effects of serotonin agonism with an increase in dopamine, ENX-105 is “well-positioned to be able to work on multiple symptoms that are really a huge unmet need in PTSD, where there's a constellation of symptoms that need to be addressed,” she added.Additionally, Engrail is developing ENX-103, a copper transport modulator to treat Menkes disease, an ultra-rare genetic condition that causes copper deficiency and is ultimately fatal.