Discovery and structure‐activity relationship study of novel series of mono‐amine transporter inhibitors for the treatment of neurodegenerative diseases

Monoamines, such as dopamine (DA), serotonin (5‐HT) and norepinephrine (NE), have an important modulatory role in neurotransmission in the central nervous system (CNS). They are involved in numerous physiological functions and pathological conditions. Therapeutic application of selective or mixed monoamine transporter (DAT, SERT or NET) inhibitors includes a variety of neurologic disorders, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, epilepsy, and others. The optimal selectivity profile varies between pathological conditions; however, the exact trend is not well understood yet. Thus, for direct comparison of produced effects, it can be beneficial to identify a class of compounds that includes structurally similar ligands with different selectivity profiles. Recently, we have serendipitously discovered a novel selective DAT inhibitor. Our compound UR118 showed strong DAT inhibition (Ki= 15 nM) with a moderate affinity to SERT (Ki= 1620nM). We design and synthesized a series of analogs of UR118 to initiate a structure‐activity relationship (SAR) study. From the first series of analogs, we obtained selective DAT inhibitors (Ki= 40), as well as DAT‐NET inhibitors (Ki= 6.5 and 167 nM, respectively). In addition to inhibition of transporters, UR118 blocked signaling of H1 (Ki= 32nM) and 5HT‐2C (Ki= 335 nM) receptors. Further, this compound did not affect the remaining 45 GPCRs in the tested panel of CNS‐related receptors. All tested analogs of UR118 have shown similar binding patterns with different selectivity profiles (data obtained from PDSP). Further, UR118 was found to moderately permeate the BBB (C max = 1000nM, 10 mg/kg, i.p in mice) with the accumulation in adipose tissue, lung, and liver. UR118 was stable in rat liver microsome (63% remaining at 1 hr.). In pertussis‐induced multiple sclerosis model (mice), we observed a significant improvement of symptoms in the UR118‐treated group when compared to the vehicle‐treated group of animals. In conclusion, we have discovered a novel series of monoamine transporter inhibitors with varying selectivity profile and favorable CNS‐drug‐like characteristics. Compound UR118 with DAT selectivity has shown definite therapeutic potential in in vivo model of multiple sclerosis. Support or Funding Information South Plains Foundation