Therefore, dual antagonists were developed as potential treatment for insomnia.78 Suvorexant (belsomra), the first-in-class dual orexin receptor antagonist, was launched in 2014.79 The second, lemborexant/E2006 (dayvigo) developed by Eisai, was approved by the FDA in 2020.80 It started from hit compound 1 (6, Fig. 3) with modest binding affinity to OX2R (Ki = 8.7 μM) and no affinity for OX1R.81 The first round of SAR studies revealed that changing the ketone group to an amide led to a remarkable enhancement (~1000-fold) of binding affinity at both OX1R and OX2R (compound 2). This evidence concerns the gene HCRTR2 and insomnia measurement.