Structural exploration of (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine analogues: identification of potent triple monoamine reuptake inhibitors as potential antidepressants.
To further explore the basic structural motifs (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine and (2S,4R,5R)-2-benzhydryl-5-(benzylamino)tetrahydro-2H-pyran-4-ol, developed by our research group, for monoamine transport inhibition, we designed and synthesized various structurally altered analogues. The new compounds were tested for their affinities for the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain by measuring their capacity to inhibit the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound 2 g exhibited a balanced potency for all three monoamine transporters (K(i): 60, 79, and 70.3 nM for DAT, SERT, and NET, respectively). In the rat forced swim test, compound 2 g produced a significant decrease in immobility in drug-treated rats relative to vehicle, indicating a potential antidepressant property.
Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48202, USA.
Soumava
S
Santra
Sanjib
S
Gogoi
Bhaskar
B
Gopishetty
Tamara
T
Antonio
Juan
J
Zhen
Maarten E A
ME
Reith
Aloke K
AK
Dutta
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011714:Pyrans; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D009638:Norepinephrine