Target-Based Drug Discovery: Discovery and Synthesis of G-Protein Biased Agonists Towards the 5-Hydroxytryptamine2A Receptor

Creating a novel, purposeful medicine through the drug discovery pipeline requires three major considerations: in vitro potency and selectivity, pharmacokinetics and pharmacodynamics (PK & PD), and safety. Typically, novel drug research begins with the identification of a healthcare gap or unmet need: for example, neuropsychiatric disorders such as depression or PTSD have become increasingly prevalent in the population, and even with current technology and medicine, there are still concerns that must be addressed. A relatively unexplored treatment angle in this particular field is the harnessing of the therapeutic properties of psychoactive compounds such as LSD or psilocybin while divorcing these benefits from their well-known hallucinogenic effects. The key aims in this review paper cover the discovery and synthesis of novel agonists towards the serotonin receptor 5-hydroxytryptamine2A (5-HT2A) inspired by psychoactive drugs and within this context, the different signaling pathways (G-protein vs. β-arrestin) of G-protein coupled-receptors (GPCRs) and the critical concept of biased agonism are discussed as playing a significant role in the discovery of potent and selective ligands (R)-69 and (R)-70. Additionally, screening methodologies to discover hit compounds and the importance of structural motifs including nitrogen heterocycles such as tetrahydropyridines (THPs) in drugs are discussed. Finally, the results of lead candidates (R)-69 and (R)-70 in animal behavioural models such as the Head Twitch Response (HTR) test and Tail Suspension Test (TST) to evaluate the efficacy and safety of the compounds are explored in this review. Although (R)-69 and (R)-70 have not undergone clinical trials, the current findings show an optimistic future perspective for the expansion of neuropsychiatric treatments in a novel direction, and this project represents an interesting case study highlighting the critical components of the drug discovery process.