Enveric Biosciences announced that it has identified three novel compounds from its EVM301 Series with the potential to offer a first-in-class approach to address difficult-to-treat disorders by promoting neuroplasticity without inducing hallucinations. Enveric plans to select one of the compounds for preclinical development early in 2024 in anticipation of Investigational New Drug application for a first-in-human clinical trial. Enveric?s research team successfully narrowed the EVM301 Series to three candidates with preclinical data indicating 5HT2A receptor binding, induction of neuroplasticity, and positive stress recovery outcomes in animal models showing no indication of hallucinations.

Enveric?s researchers leveraged the Company?s proprietary computational chemistry and artificial intelligence drug-discovery platform, PsyAI? to simulate interactions between indolethylamine derivatives and the 5HT2A receptor to design novel molecules with reduced head-twitch response in mice. Predicted structures were initially screened for patentability and freedom-to-operate to complement Enveric?s extensive intellectual property portfolio covering indolethylamine structures and their fields of use.

From a pool of more than 100 designed molecules, 44 new chemical entities were synthesized and screened using the HTR hallucination model. Most compounds displayed reduced HTR, and three candidates that showed what is believed to be insignificant HTR across a wide dose range, yet still induced neuroplasticity and bound to the 5HT2A receptor, were selected. The three candidates showed 5HT2A binding affinity between 1 and 3 micromolar, generally displayed partial agonism in functional cell-based assays with respect to the 5HT2A-Gq pathway and promoted robust structural neuronal plasticity from a single dose.

Each candidate was further assessed for numerous pharmaceutically relevant criteria. Analysis on serum drawn from mice subjected to intraperitoneal injection revealed diversity in the candidate compound pharmacokinetic profiles, providing optionality for future method of administration development. All three candidates demonstrated acceptable assessments of cellular toxicity, blood-brain barrier permeability, and differential binding to other serotonin receptors and transporters.

In mouse efficacy models, a single 10 mg/kg dose of any of the three candidates promoted the general recovery of stressed mice to non-stressed behaviors in sucrose-preference and marble-burying models of depression and anxiety, respectively, one day and one week after treatment.