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A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.

Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.

Bioisosteric replacement studies led to the identification of N -(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide (( S )- 3 ) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)- N -[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide (( S )- 4 ), and N -[1-(2,3-dihydro-1 H -indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide (( S )- 5 ) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 μM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (±)- 3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds ( S )- 4 and ( S )- 5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.

A number of N-substituted 1-(5-fluoro-2-pyrimidinyl)piperazine derivatives were prepared and evaluated for binding to sigma and serotonin 5-HT 1A and 5-HT 2 receptor subtypes as well as for their protection against nitrogen anoxia-induced lethality in rats. Although various compounds exhibited good binding affinity and/or anti-anoxic effects, there was no obvious correlation between their receptor binding and in vivo effects.