Discovery of <i>N</i>‑Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications

A series of <i>N</i>-substituted (2-phenylcyclopropyl)­methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT_2C)-selective agonists with a preference for G_q signaling. A number of these compounds exhibit 5-HT_2C selectivity with a preference for G_q-mediated signaling compared with β-arrestin recruitment. Furthermore, the <i>N-</i>methyl compound (+)-<b>15a</b>, which displayed an EC₅₀ of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT_2C agonist reported to date. The <i>N</i>-benzyl compound (+)-<b>19</b>, which showed an EC₅₀ of 24 nM at the 5-HT_2C receptor, is fully selective over the 5-HT_2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-<b>19</b> showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT_2C receptor with respect to antipsychotic activity