Synthesis and hSERT activity of homotryptamine analogs. Part 6: [3+2] dipolar cycloaddition of 3-vinylindoles.
Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET.
Marcin
Lawrence R
LR
Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Mattson
Ronald J
RJ
Gao
Qi
Q
Wu
Dedong
D
Molski
Thaddeus F
TF
Mattson
Gail K
GK
Lodge
Nicholas J
NJ
D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000138:chemical synthesis* / Q000378:metabolism*; D014363:Tryptamines / Q000138:chemical synthesis* / Q000378:metabolism*
D007211:Indoles; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D014363:Tryptamines; C030820:tryptamine