Discovery of NLX-266, an Orally Available and Metabolically Stable ERK1/2-Biased 5-HT<sub>1A</sub>R Agonist with Superior Antidepressant and Antiparkinsonian Activity.

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We report the discovery of NLX-266 (31), an orally available and metabolically stable ERK1/2-biased 5-HT1A receptor agonist, which demonstrates both enhanced antidepressant and antiparkinsonian-like activities. A new series of 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were synthesized and screened for their affinity and selectivity toward the 5-HT1A receptor. Notably, 31 exhibited exceptional binding affinity (pKi > 10) and selectivity (>1000×) over the adrenergic α1 and dopaminergic D2 receptors. In vitro functional assays revealed that 31 preferentially activates ERK1/2 phosphorylation, correlating with significant antidepressant effects in the forced swim test in rats at low doses (MED = 0.63 mg/kg p.o.). Furthermore, 31 demonstrated potent antiparkinsonian effects by reversing haloperidol-induced catalepsy at very low doses (MED = 0.04 mg/kg p.o.). The pharmacokinetic profile of 31 indicates favorable exposure and a prolonged half-life following oral administration. These findings suggest that 31 is a promising candidate for future exploration aiming at treatment of depression and/or Parkinson's disease.

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