| Summary: | Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (<i>h</i>TAAR1) ligands, we synthesized a new series of 1-amidino-4-phenylpiperazine derivatives (<b>1</b>–<b>16</b>) based on the application of a combined pharmacophore model/scaffold simplification strategy for an in-house series of biguanide-based TAAR1 agonists. Most of the novel compounds proved to be more effective than their prototypes, showing nanomolar EC<sub>50</sub> values in functional activity at <i>h</i>TAAR1 and low general cytotoxicity (CC<sub>50</sub> > 80 µM) when tested on the Vero-76 cell line. In this new series, the main determinant for TAAR1 agonism ability appears to result from the appropriate combination between the steric size and position of the substituents on the phenyl ring rather than from their different electronic nature, since both electron-withdrawing and electron donor groups are permitted. In particular, the <i>ortho</i>-substitution seems to impose a more appropriate spatial geometry to the molecule that entails an enhanced TAAR1 potency profile, as experienced, in the following order, by compounds <b>15 </b>(2,3-diCl, EC<sub>50</sub> = 20 nM), <b>2 </b>(2-CH<sub>3,</sub> EC<sub>50</sub> = 30 nM), <b>6 </b>(2-OCH<sub>3,</sub> EC<sub>50</sub> = 93 nM) and <b>3 </b>(2-Cl, EC<sub>50</sub> = 160 nM). Apart from the interest in them as valuable leads for the development of promising <i>h</i>TAAR1 agonists, these simple small molecules have further allowed us to identify the minimal structural requirements for producing an efficient <i>h</i>TAAR1 targeting ability.
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