Science

functionally Selective Neuropsychiatric Drugs:

The importance of G_q signaling bias

G-coupled protein receptors (GPCRs) can activate multiple downstream signaling pathways, including the β-arrestin pathway.  Nevertheless, it has recently been recognized that certain ligands can exhibit “functional selectivity” for one pathway over the other, wherein the ligand induces preferential signaling through either the GPCR or β-arrestin. For example, in the case of the 5-HT2C receptor, a “functionally selective” ligand can preferentially induce signaling via G_q-mediated calcium flux with no (or greatly reduced) signaling events modulated by the β-arrestin pathway.  β-arrestin was initially named for its ability to turn off GPCR signaling, and its recruitment is responsible for desensitization, internalization, and eventual degradation of GPCRs.  Accordingly, it has been shown that a bias for GPCR-mediated signaling can provide an improved mechanism of action (MOA) for developing improved therapeutics with reduced side effects and off-target liability.

The µ-opioid receptor (MOR) agonist Oliceridine [TRV130; Olinvyk®] was approved as the first “G-protein biased” drug by the FDA in 2020 for the treatment of acute pain. Morphine, fentanyl, and oxycodone provide powerful analgesia through the MOR, but their clinical utility is greatly complicated by negative side effects linked directly to non-selective G_i signaling and robust β–arrestin recruitment. Oliceridine is a potent analgesic that exerts reduced gastrointestinal dysfunction and respiratory depression at equianalgesic doses compared to morphine. The reduced side effects of Oliceridine have been linked to its G_i signaling bias and minimal levels of β-arrestin recruitment.

The FDA-approved drug lorcaserin (Belviq®) was touted as a “selective” 5-HT2C agonist to treat obesity. However, after entering the market, many patients developed a tolerance to its anorectic effects. While lorcaserin has some level of selectivity for the 5-HT2C receptor over the other 12 known serotonin receptor subtypes, it lacks “functional selectivity” because it strongly activates both G_q-mediated signaling and β-arrestin recruitment.  A robust positive correlation for magnitude of 5–HT2C desensitization and β–arrestin recruitment has been identified as the primary reason for the tolerance developed by patients.

Vabicaserin (Pfizer), a selective 5-HT2C agonist, was a Phase II clinical candidate that was well tolerated by hospitalized patients with schizophrenia with no significant safety concerns and no weight gain. 200 mg/day demonstrated efficacy compared to placebo at antipsychotic endpoints, but 400 mg/day dose did not. Clinical trials of vabicaserin were terminated early for an alleged failure to meet the primary efficacy objective.  To our knowledge, vabicaserin was never screened to probe whether or not it induces a biased signaling mechanism. However, through our own research, we have demonstrated vabicaserin is an unbiased activator of both G_q and β-arrestin via the 5-HT2C receptor.  From this, we postulate that vabicaserin’s lack of functional selectivity likely explains its failure to meet therapeutic endpoints.