RO-5263397

Current treatments for alcohol use disorder have limited efficacy underscoring the need for novel therapeutic targets. Trace amine-associated receptor 1 (TAAR1) is a promising candidate due to its ability to act as a brake on dopaminergic transmission and alcohol consumption. However, both the relative efficacy of full and partial TAAR1 agonists in reducing alcohol-related behaviors and their underlying mechanisms of action remain unclear. In this study, we evaluated the effects of the full agonist RO5166017 and the partial agonist RO5263397 on alcohol consumption using an intermittent access protocol in alcohol-preferring male C57BL/6JRj mice. Given their distinct pharmacological and electrophysiological properties, we also investigated the effects of these agonists on presynaptic dopaminergic transmission using fast-scan cyclic voltammetry in the nucleus accumbens, a key structure involved in alcohol reinforcement. Full and partial TAAR1 agonists reduced alcohol intake by 25 % and 43 %, respectively. We further report that these agonists exhibit opposite effects on dopamine release under basal conditions, but that these effects are reversed in animals chronically exposed to alcohol. The reversal in dopamine release did not result from alcohol-induced modifications of TAAR1 or D2 receptor expression. Our findings highlight the therapeutic potential of TAAR1 agonists for alcohol addiction and reveal important functional differences between full and partial agonists. Further research is needed to determine the clinical relevance of these distinct pharmacodynamic profiles and optimize TAAR1-targeting pharmacotherapies.

Density functional theory studies of TAAR1 (trace amine associated receptor 1) partial agonist RO5263397 carried out with precise and detailed spectroscopic investigation as well as validated experimentally. FT-IR, confocal Raman and UV-visible spectroscopic techniques were used to characterize the compound and corresponding theoretical calculations were carried out using DFT/B3LYP method with 6-311++G (d,p) basis set. Estimated and observed vibrational wavenumbers of the compound were assigned. UV-visible spectrum and FMOs (frontier molecular orbital) analysis reveals that the polarity affects the molecular reactivity and stability of the compound. Donor - acceptor interaction and second order perturbation energy have been explained using natural bond orbital analysis clarify the presence hydrogen bonds in the system. ELF and LOL studies visualises the localized and delocalized electrons in the title compound. RDG analysis evidences the various interactions present in the monomer and dimer of RO5263397. The structural importance of the compound were clearly examined using NMR spectral analysis. The existence of hydrogen bonding is validated by reactive site findings from Mulliken atomic charge distribution and molecule electrostatic potential surface studies. Information about distinct drug-receptor interactions obtained from molecular docking investigation offers the path of further study of molecular activity in various drug-receptor mechanism.