Development of potent dopamine–norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template

Abstract

Current therapy of depression is less than ideal with remission rates of only 25–35% and response rates of 45–60%. It has been hypothesized that a dysfunctional dopaminergic system in the mesocorticolimbic pathway in depressive disorder may lead to development of anhedonia associated with loss of pleasure and interest along with loss of motivation. The current antidepressants do not address dopamine dysfunction which might explain their low efficacy. In this report, we have described an SAR study on our pyran-based triple reuptake inhibitors (TRIs) which are being investigated as the next-generation antidepressants. In the present work we demonstrate that our lead TRIs can be modified with appropriate aromatic substitutions to display a highly potent SSRI profile for compounds 2a and 4a (Ki (SERT); 0.71 and 2.68 nM, respectively) or a potent DNRI profile for compounds 6b and 6h (Ki (DAT/NET); 8.94/ 4.76 and 13/ 7.37 nM, respectively). Compounds 4g–4i exhibited potencies at all three monoamine transporters. The results provide insights into the structural requirements for developing selective dual- and triple-uptake inhibitors from a unique pyran molecular template for an effective management of depression and related disorders.

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

“…Chemical shifts are expressed in δ values (ppm) with tetramethylsilane (δ 0.00) for CDCl 3 and water (δ 3.30) for CD 3 OD. NMR spectra were collected with a Bruker AV spectrometer equipped with a z-gradient [ 1 H, 13 C, 15 N]-cryoprobe. TLC analysis was carried out on glass sheets precoated with silica gel F254 (0.2 mm) from Sigma-Aldrich.…”

Novel serotonin transporter regulators: Natural aristolane- and nardosinane- types of sesquiterpenoids from Nardostachys chinensis Batal

“…SERT inhibitors (SIs) are dominant containing tricyclic antidepressants, selective serotonin reuptake inhibitors and selective noradrenaline reuptake inhibitors 29 , while the selective enhancer of SERT is rare and the only one in clinical use is tianeptine 30 . So far, hundreds of known SIs 31 – 52 , including 3-(aminoalkyl)-5-fluoroindole 53 , have been developed by chemical modification or hybridization of the known clinical antidepressants, based on the molecular templates shown in Fig. 4 .…”

Novel Potent Dopamine–Norepinephrine and Triple Reuptake Uptake Inhibitors Based on Asymmetric Pyran Template and Their Molecular Interactions with Monoamine Transporters

“…In another line of experiments, we developed a number of potent DNRI-type compounds which gave us an indication for the structural requirement for such an activity in pyran derivatives. 21,26 Our proposed model from such SAR studies indicated the importance of certain molecular features for either a DNRI or a TRI profile. 21,26 The current study is a follow up on these earlier SAR studies in order to further map out structural requirements for the interaction of pyran compounds with monoamine transporters through their binding activities and analyzing mode of interactions through molecular docking studies at the transporters binding pockets.…”