ABSTRACT
The title compound, 4-hy-droxy-N-iso-propyl-tryptamine (4) or 4-HO-NiPT (systematic name: 3-{2-[(propan-2-yl)amino]-eth-yl}-1H-indol-4-ol), C13H18N2O, was synthesized in three steps from 4-benzyl-oxyindole (1) (systematic name: 4-phen-oxy-1H-indole), C15H13NO. (1) was treated with oxalyl chloride and iso-propyl-amine to produce N-isopropyl-4-benz-yloxy-3-indole-glyoxyl-amide (2) {systematic name: 2-[4-(benz-yloxy)-1H-indol-3-yl]-2-oxo-N-(propan-2-yl)acet-amide}, C20H20N2O3. (2) was reduced to generate 4-benz-yloxy-N-iso-propyl-tryptamine (3) or 4-HO-NiPT, which was characterized as its chloride salt 4-benz-yloxy-N-iso-propyl-tryptammonium chloride (3a) (systematic name: {2-[4-(benz-yloxy)-1H-indol-3-yl]eth-yl}(propan-2-yl)aza-nium chloride), C20H25N2O·Cl. Finally the benzyl group of (3) was removed via hydrogenation to generate 4-HO-NiPT. The crystal structures of the title compound and all three synthetic precursors are presented.
ABSTRACT
A novel class of isochroman dopamine analogues, originally reported by Abbott Laboratories, have >100-fold selectivity for D1-like over D2-like receptors. We synthesized a parallel series of chroman compounds and showed that repositioning the oxygen atom in the heterocyclic ring decreases potency and confers D2-like receptor selectivity to these compounds. Inâ silico modeling supports the hypothesis that the altered pharmacology for the chroman series is due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxy group of the catechol moiety. This interaction realigns the catechol hydroxy groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds. Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity are restored.
