Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

Abstract

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure−activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forcedswim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/ kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

“…[ 169 ] Then they further investigated a series of novel 4‐bicyclic heteroaryl THIQ derivatives as TRIs based on the lead compound 121 . [ 170 ] The SARs studies indicated that substitution at the 7‐position of the THIQ enhanced inhibitory properties for three monoamine transporters, and compound 122 showed better inhibitory activity with IC 50 values of 3.0, 8.3, and 3.1 × 10 −9 m for hSERT, hNET, and hDAT, respectively. In addition, compound 122 displayed much reduced CYP2D6 inhibition (IC 50 = 11 × 10 −6 m ) and low hERG inhibitory activity with an IC 50 value of 1 × 10 −6 m .…”

“…Moreover, (+)‐enantiomer displayed more potency at three transporters than (−)‐enantiomer at 4‐position of the THIQ scaffold. [ 169,170 ]…”

Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs – biological activities and SAR studies

“…In subsequent studies, novel THIQ analogs were designed by taking cues from compound 209. 84 This series of compounds explored the substitution of different heterobicyclic groups on the 4-position of the THIQ nucleus. Substitution with heterobicyclic groups gave rise to compounds that were capable of inhibiting NET, DAT, and Serotonin transporter (SERT), thus giving rise to triple reuptake inhibitors.…”

Synthesis and biological evaluation of novel benzothiophene derivatives

“…16 Recently, a number of 3-(4-pyridinyl) amino benzothiophenes, which were selective serotonin re-uptake inhibitors, have been tested for their contribution on the treatment of central nervous system disorders such as Alzheimer's disease. 17 Therefore, synthetic and medicinal chemists have tried to find novel organic compounds containing sulfur atoms for decades.…”