2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction. KEYWORDS: TAAR1 agonist, 2-aminooxazoline, SAR, schizophrenia T race amines (TAs) are metabolites of amino acids with structural similarity to biogenic amines and represent the endogenous ligands of the trace amine associated receptor 1 (TAAR1). 1,2 Dysregulation of TAs in the brain has been linked to a variety of psychiatric diseases and selective TAAR1 ligands have gained much interest as potential therapeutics for depression, schizophrenia, bipolar disorder, ADHD, and psychostimulant addiction. 3 The modulatory role of this G protein-coupled receptor on monoaminergic neurotransmission has recently been investigated and confirmed by characterization of a transgenic mouse line overexpressing TAAR1 in central nervous system neurons. 4 Further efforts were made to identify potent and selective TAAR1 agonists with favorable pharmacokinetic properties in order to prove the modulatory effect on dopaminergic signaling in vivo. 5 In an endeavor to discover a novel and selective TAAR1 chemotype, we considered application of the SOSA approach (Selective Optimization of Side Activities) to adrenergic ligands as a viable lead identification strategy. 6 Structural similarity of TAAR1 agonists with adrenergic agonists was already known from our previous work 5 pointing toward a similarity of the binding regions of both receptors. 7,8 Therefore, we searched the literature and in-house databases for adrenergic ligands reported as drugs or development candidates, whereupon the alpha 2 adrenergic receptor partial agonist S18616 from Servier (1) caught our attention. 9 Pleasingly, testing this candidate revealed (besides its expected activity at the human α 2A receptor) a high functional activity at human TAAR1 (EC 50 = 15 nM). 10 A medicinal chemistry optimization program was then started aiming for compounds selective for TAAR1, where the known TAAR1 pharmacophore motif (aromatic moiety linked to a basic headgroup) of S18616 was kept, but the linker region was modified by opening the central six-membered ring (Figure 1). For all such derived compounds selectivity data was obtained by measuring functional activity at the human TAAR1 receptor (EC 50 hTAAR1) and in addition at the human adrenergic α 2A receptor (hα 2A ) (Table 1).All 2-aminooxazolines were synthesized from the corresponding amino alcohols 15 and cyanogen bromide in the presence of a base as depicted in Scheme 1. The enantiomerically pure amino alcohols were obtained from the chiral pool (e.g., via reduction of amino acids or their derivatives). The procedures are describ...